CA2903569C

CA2903569C - Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides and their use as inhibitors of cathepsin c

Info

Publication number: CA2903569C
Application number: CA2903569A
Authority: CA
Inventors: Ralf Anderskewitz; Matthias Grauert; Marc Grundl; Peter Wilhelm HAEBEL; Thorsten Oost; Alexander Pautsch; Stefan Peters; Florian Binder; Viktor VINTONYAK
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2013-03-14
Filing date: 2014-03-12
Publication date: 2023-04-11
Anticipated expiration: 2034-03-12
Also published as: PH12015501964A1; CN105026395A; EP2970283B1; UY35391A; HK1211579A1; IL240030B; CA2903569A1; PH12015501964B1; EA201500923A1; PE20151727A1; US20170266160A1; PL2970283T3; MX2015011799A; JP6689805B2; WO2014140075A1; AP2015008601A0; TW201522307A; US9713606B2; DK2970283T3; TN2015000381A1

Abstract

This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)- amides of formula (1) and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

Description

SUBSTITUTED 2-AZA-BICYCLO[2.2.1]HEPTANE-3-CARBOXYLIC ACID (BENZYL-CYANO-METHYL)-AMIDES AND THEIR USE AS INHIBITORS OF CATHEPSIN C
FIELD OF INVENTION
This invention relates to substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1 (R1)2 H N
N

and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.
BACKGROUND INFORMATION
= W02004110988 discloses peptidyl nitrite inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the treatment of a series of diseases.
= W02009074829 and W02010142985 also disclose peptidyl nitrite inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the treatment asthma, COPD or allergic rhinitis.
BRIEF SUMMARY OF THE INVENTION
Dipeptidyl-aminopeptidase I (DPPI or Cathepsin C; EC3.4.141), is a lysosomal cysteine protease capable of removing dipeptides from the amino terminus of protein substrates.
DPPI was first discovered by Gutman and Fruton in 1948 (J. Biol. Chem 174: 851-858, 1948).
The cDNA of the human enzyme has been described in 1995 (Paris et al.; FEBS Lett 369: 326-330, 1995). The DPPI
protein is processed into a mature proteolytically active enzyme consisting of a heavy chain, a light chain, and a propeptide that remains associated with the active enzyme (Wolters et al.; J. Biol. Chem.
273: 15514-15520, 1998). Whereas the other cysteine Cathepsins (e.g. B, H, K, Land S) are Date Recue/Date Received 2020-08-20

2 monomers, DPPI is a 200-kD tetramer with 4 identical subunits, each composed of the 3 different polypeptide chains. DPPI is constitutively expressed in many tissues with highest levels in lung, kidney, liver and spleen (Kominami et al.; Biol. Chem. Hoppe Seyler 373: 367-373, 1992).
Consistent with its role in the activation of serine proteases from hematopoetic cells, DPPI is also relatively highly expressed in neutrophils, cytotoxic lymphocytes, natural killer cells, alveolar macrophages and mast cells. Recent data from DPPI deficient mice suggest that, besides being an important enzyme in lysosomal protein degradation, DPPI also functions as the key enzyme in the activation of granule serine proteases in cytotoxic T lymphocytes and natural killer cells (granzymes A and B; Pham et al.; Proc. Nat. Acad. Sci 96: 8627-8632, 1999), mast cells (chymase .. and tryptase; Wolter et al.; J Biol. Chem. 276: 18551-18556, 2001), and neutrophils (Cathepsin G, elastase and proteinase 3; Adkison et al.; J Clin. Invest. 109: 363.371, 2002). Once activated, these proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.
.. Thus, inhibitors of Cathepsin C could potentially be useful therapeutics for the treatment of neutrophil-dominated inflammatory diseases such as chronic obstructive pulmonary disease (COPD), pulmonary emphysema, asthma, multiple sclerosis, and cystic fibrosis (Guay et al.; Curr.
Topics Med. Chem. 10: 708-716, 2010; Laine and Busch-Petersen; Expert Opin.
Ther. Patents 20:
497-506, 2010). Rheumatoid arthritis is also another chronic inflammatory disease where DPPI
.. appears to play a role. Neutrophils are recruited to the site of joint inflammation and release Cathepsin G, elastase and proteinase 3, proteases which are believed to be responsible for cartilage destruction associated with rheumatoid arthritis. Indeed, DPPI deficient mice were protected against acute arthritis induced by passive transfer of monoclonal antibodies against type II collagen (Adkison et al.; J Clin. Invest. 109: 363.371, 2002).
In light of the role DPPI plays in activating certain pro-inflammatory serine proteases, it seems desirable to prepare compounds that inhibit its activity, which thereby inhibit downstream serine protease activity. It has been surprisingly found that the bicyclic compounds of the present invention possess potent Cathepsin C activity, high selectivity against other Cathepsins, e.g.
Cathepsin K, and in general desirable pharmacokinetic properties.
DETAILED DESCRIPTION OF THE INVENTION
A compound of formula 1

3 (R1)i.H N

wherein R1 is independently selected from H, Ci_6-alkyl-, halogen, HO-, Ci_6-alkyl-0-, H2N-, C1_6-alkyl-HN- and (Ci_6-alky1)2N-, C1_6-alkyl-C(0)HN-;
or two Ri arc together C1_4-alkylene;
R2 is selected from io = R2'1;
= aryl-; optionally substituted with one, two or three residues independently selected from R2';
optionally substituted with one R2'1;
= C5_10-heteroaryl-; containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R21; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.2; wherein a carbon atom of the ring is optionally substituted with one R23; a nitrogen atom of the ring is optionally substituted with one R24;
and = C5 10-heterocycly1-; containing one, two, three or four heteroatoms independently selected from S. S(0), S(0)2, 0 and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three or four R2.1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R22;
wherein a carbon atom of the ring is optionally substituted with one R2.3 or one R25; a nitrogen atom of the ring is optionally substituted with one R24 or = R2 and R4 are together with two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1;
wherein

4 nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2-2;
R2.1 is independently selected from among H, halogen, NC-, 0=, HO-, H-A-, H-A-Ci_6-alkylene-, C1_6-alkyl-A-, C3_8-cycloalkyl-A-, C1_6-haloalkyl-A-, R2.1.1-C1_6-alkylene-A-, C1_6-alkyl-A-C1_6-alkylene-, C3_8-cycloalkyl-A-C1_6-alkylene-, HO-C1_6-alkylene-A-, HO-C 1_6-alkylene-A-C1_6-alkylene-, Ci_6-alkyl-O-C1_6-alkylene-A- and C1_6-alkyl-O-C1_6-alkylene-A-C1_6-alkylene-;
R2.1.1 is independently selected from = aryl-; optionally substituted independently from each other with one, two or three R21.1.1;
= C5_10-heteroaryl-; containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1-1-1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2-1-12;
= G_Io-heterocycly1-; containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three or four R2J-1-1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2'12;
R2.1.I.1 is independently selected from among halogen, HO-, 0=, C _6-alkyl-, C1_6-alkyl-0-, C1_6-haloalkyl-, C1_6-haloalky1-0- and C3_8-cycloalkyl-;
R2.1.1.2 is independently selected from among 0=, C1_6-haloalkyl-; C3_8-CyCloalkyl-, C1_6-alkyl-O-C1_6-alkyl-, H(0)C-,

5 PCT/EP2014/054794 tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;
R2.2 is independently selected from among H-A-C1_6-alkylene-, C3_8-cycloalkyl-, 5 C1_6-alkyl-A-C1_6-alkylene-, C3_8-cycloalkyl-A-C1_6-alkylene-, C1_6-haloalkyl-A-C1_6-alkylene-, R2-1=1-A-C1_6-alkylene-, C1_6-alkyl-S(0)2-, C1_6-alkyl-C(0)- and R2'1=1-A-;
R23 and R4 are together selected from among -0-, - S-, -N(R23 1)-, -C(0)N(R2-'1-1)-, -N(R2-3-1)C(0)-, -S(0)2N(R23'1)-, -N(R23'')S(0 )2-, -C(0)0-, -0C(0)-, -C(0)-, -S(0)-, -S(0)2-, R23, R23, -C(R2.3.2)=C(R23.)-, -C=N-, -N=C-, -C(R2'3'2)2-0-, -0-C(R2'3'2)2-, -C(R2.3.2)2N(R2.3.1)-, -N(R2.3.1)C(R22)2- and -C1_4-alkylene-;
R2.3.1 is independently selected from among H, C1_6-alkyl-, C1_6-haloalkyl-;
Cm-cycloalkyl-, H2N-C1_4-alkylene-, (C1_4-alkyl)HN-C1_4-alkylene- and, (C1_4-alky1)2N-C1_4-alkylene-;
R2.3.2 is independently selected from among H, C1_6-alkyl-, C1_6-haloalkyl-;
C3_8-cycloalky1-, HO-C1_4-alkylene-, (C1_4-alkyl)-0-C1_4-alkylene-, H2N-C14-alkylene-, (C1_4-alkyl)HN-C1_4-alkylene- and (C1_4-alky1)2N-C1_4-alkylene-;
R24 and R4 are together selected from (R2.4.])_, (R..1)_ among-N -C(0)N24 , -N(R2-4-' )C(0)-, -S(0)2N(R2-4-1)-, -N(R2-4-I)S(0)2-, -C(0)-, -S(0)-, -S(0)2-, -C(R242)=C (R242)-, _ C=N-, -N=C-, -C(R242)2N(R2.4.1)_, _N(R2.4.1)c (R2.4.2 )2- and -C1_4-alkylene-; and R2.4.1 = is independently selected from H, C1_6-alkyl-, C1_6-haloalkyl-;
C3_8-cycloalkyl-, HO-C1_4-alkylene-, (C1_4-alkyl)-0-C1_4-alkylene-, (Ci_4-alkyl)HN-C1_4-alkylene-, (Ci_4-alky1)2N-C1_4-alkylene-;

6 R2.4.2 is independently selected from H, Ci_6-alkyl-, C _6-haloalkyl-;
C3_8-cycloalkyl-, HO-C1A-alkylene-, (C1A-alkyl)-0-CIA-alkylene-, H2N-CI4-alkylene-, (CIA-alkyl)HN-CIA-alkylene- and (C1A-alky1)2N-C1A-alkylene-;
R2.5 and R4 arc together selected from -C(R2.5.1)=, =C(R2.5.1)- and -N=; and R2.5.1 is independently selected from H, Ci_6-alkyl-, C1_6-haloalkyl-;
C3_8-cyclo alkyl-, HO-C14-alkylene-, (C 14-alkyl)-0-C14-alkylene-, H2N-C14-alkylene-, (C1A-alkyl)HN-C1A-alkylene- and (CIA-alky1)2N-CIA-alkylene-;
R3 is H or F;
R4 is independently selected from F, Cl, phenyl-H2C-0-, HO-, C1_6-alkyl-, C1_6-haloalkyl-, C3_8-cycloalkyl-, Ci_6-alkyl-0-, C1_6-haloalky1-0-, C1_6-alkyl-HN-, (C1_6-alky1)2-HN-, C1_6-alkyl-HN-CIA-alkylene- and (Ci..6-alky1)2-HN-CIA-alkylene-;
A is a bond or independently selected from -0-, - S-, -N(R5)-, -C(0)N(R5)-, -N(10C(0)-, -S(0)2N(10-, -N(R5)S(0)2-, -S(0)(=N
R5)-N(R)-, -N(R5)(NR5=) S(0)-, -S(=NIV)2-N(R')-, -N(R5)(NR5=)2S-, -C(R5)=C(R5)-, , -C(0)0-, -0C(0)-, -C(0)-, -S(0)-, -S(0)2-, -S(=NR5)-, -S(0)(=NR.5)-, -S(=NR5)2-, -(R.5)( 0)S=N-, -(R5N=)(0)S- and -N=(0)(R5)S-;
R5 is independently selected from H, C16-alkyl-and NC-;
or a salt thereof.
PREFERRED EMBODIMENTS
Preferred are the above compounds of formula 1, wherein R1 is Ri.a and R1' is independently selected from H, C14-alkyl-, F and HO-.
Preferred are the above compounds of formula 1, wherein R1 is Rl.b and Rl.b is H.

7 Preferred are the above compounds of formula 1, wherein RI is Rl'e and two Ri'' are together -CH2-.
Preferred are the above compounds of formula 1, wherein R2 is Rla and R2'a is R2.1.
Preferred arc the above compounds of formula 1, wherein R2 is R2.b and R2.b is R2.1.a.
Preferred are the above compounds of formula 1, wherein R2 is Rle and R2'e is aryl-, optionally substituted with one, two or three residues independently selected from R2-1;
optionally substituted 1() with one R2.
Preferred are the above compounds of formula 1, wherein R2 is R2'd and R2'd is phenyl; optionally substituted with one, two or three residues independently selected from R2'1;
optionally substituted with one R23.
Preferred are the above compounds of formula 1, wherein R2 is RI(' and R2'd is phenyl; optionally substituted with one, two or three residues independently selected from R2'1 and R2.1 is R2'1' and R2'1" is selected from H, halogen, NC-, 0=, HO-, H-A-, R2.1'1-A-, C3_6-cycloalkyl-A-, C1_4-haloalkyl-A-, R2'1=1-Ci_4-a1kylene-A-, C1_4-alkyl-A-C1_4-alkylene-, C3_6-cycloalkyl-A-C1_4-alkylene-, C1_4-haloalkyl-A-C1_4-alkylene-, R2'1=1-C1_4-alkylene-A-C1_4-alkylene-, R2.1.1-A-C1_4-alkylene-, HO-Ct_4-alkylene-A-, HO-C1_4-alkylene-A-C1_4-alkylene-, Ci_4-alkyl-O-Ci_4-alkylene-A- and Ci_4-alkyl-O-Ci_4-alkylene-A-Ci_4-alkylene-;
and R2-1-1 is R2.1.1 and R2.I La is selected from = aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2'1=1=1;
= C5_10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R211.1;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2'12;

8 = C5_10-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1=1=1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.12;
and R2.1.i.1 is independently selected from halogen, HO-, 0=, Cm-alkyl-, C14-alkyl-0-, CI_ 4-haloalkyl-, C14-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, Cm-alkyl-, C1_4-haloalkyl-; C3_6-cycloalkyl-, CI-4-alkyl-O-Cm-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
Preferred are the above compounds of formula 1, wherein R2 is RIg and R24 is selected from yON 7S zs H
N, 0, H

7 1/ N __ N
/

\ N --- \ le -....-- "----- N NI N H /
-_---`>.-..,, H S H -õ,N-N
N'''''-=:-----N
N and , wherein carbon atoms of the ring are optionally and independently from each other substituted with zo one, two or three R21, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2; and R2.1 is R2'1 and R2.1.a. is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-Cm-alkylene-, R2.1.1-A-, Cm-alkyl-A-, C3_6-cycloalkyl-A-, Cm-haloalkyl-A-, R2'1'1-Ci_4-a1kylene-A-, Cm-alkyl-A-Cm-alkylene-, C3_6-cycloalkyl-A-Cm-alkylene-, Ci_4-haloalkyl-A-C14-alkylene-, R2'1'1.-C1_4-alkylene-A-C1_4-alkylene-, R2.1.1-A-C1_4-alkylene-, HO-C t_4-alkylene-A-, HO-Cm-alkylene-A-C1_4-alkylene-, C14-alkyl-O-C14-alkylene-A- and C14-alkyl-O-C14-alkylene-A-CIA-alkylene-; and

9 R2.1.1 is R2.1.1.a and R2.1.1.a.
is selected from = aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2'1=1=1;
= C5_10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)7, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1=1=1;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2. I.1 .2; and = C5_10-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1=1=1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2'Ll'2;
and R2.1.1.1 is independently selected from halogen, HO-, 0=, C14-alkyl-, C14-alkyl-0-, CI_ C14-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C1A-alkyl-, C14-haloalkyl-; C3_6-cycloalkyl-, C1 4-alkyl-O-C1A-alkyl-, H(0)C-, C1A-alkyl-(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R2.2 is R2.2.a and R2.2.a is independently selected from H-A-C1A-alkylene-, C3_6-cycloalkyl-, Ci_4-alkyl-A-C1A-alkylene-, C3_6-cycloalkyl-A-C1_4-alkylene-, CIA-haloalkyl-A-C1A-alkylene-, R2.1.1-A-CI4-alkylene-, CiA-alkyl-S(0),,- and C1A-alkyl-C(0)-, R2-' -1-A-.
Preferred are the above compounds of formula 1, wherein R2 is R2'e and R2'e is C501 6-heteroaryl-, containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2A; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.2; wherein a carbon atom of the ring is optionally substituted with one R23; a nitrogen atom of the ring is optionally substituted with one R2A.

Preferred are the above compounds of formula 1, wherein R2 is R21 and R21 is bicyclic C7_10-heteroaryl-, each containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1; wherein nitrogen atoms of the ring are optionally 5 and independently from each other substituted with one, two or three R2.2; wherein a carbon atom of the ring is optionally substituted with one R2'3; a nitrogen atom of the ring is optionally substituted with one R24 .
Preferred are the above compounds of formula 1, wherein R2 is R2'g and R2'g is selected from ,ON
N, 0, N, \ N N
NH
N
wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R21, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R22; wherein a carbon atom of the ring is optionally substituted with one R2'3; a nitrogen atom of the ring is optionally substituted with one R24 .
Preferred are the above compounds of formula 1, wherein R2 is R231 and R211 is selected from zo pyrazole, thiopheneand furane, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2-1, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R22; wherein a carbon atom of the ring is optionally substituted with one R2.3; a nitrogen atom of the ring is optionally substituted with one R24 .
Preferred are the above compounds of formula 1, wherein R2 is R2'1 and R.2-1 is selected from C6-heterocyclyl- and C7_10-heterocycly1-, each containing one, two, three or four heteroatoms independently selected from S, 0 and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R21; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R22; wherein a carbon atom of the ring is optionally substituted with one R23 or one R2.5; a nitrogen atom of the ring is optionally substituted with one R24 .
Preferred are the above compounds of formula 1, wherein R2 is R2.j and R2.j is selected from H H H H H H N N ,...N -.....õ
H õ.. N -..., H N
-.. N.-''. ..- g 9 ..,___ N N N
\/- H 0 H H H
, , , , , , H
N

N H CiiiIIN
H 0>, , , , , N
0.NH ,N1H HNXNH
S and , , to wherein carbon atoms of the ring arc optionally and independently from each other substituted with one, two or three R2.1, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2; wherein a carbon atom of the ring is optionally substituted with one R2:3 or one R25; a nitrogen atom of the ring is optionally substituted with one R24.
Preferred are the above compounds of formula 1, wherein R2 is R2i and R2i is selected from H H H H H N N
H
......N -..._ H ,.. N --..., H
N,.. N -.......
". N /
/ _ N N N

, , , , , , , , H
N
H, N H, 0 0>
N N
H
, , , N
,NH HNXNH
0,,NH
S and , , wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2-1; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2; and R2.1 is R2.1.a and R2.1' is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-C14-alkylene-, C3_6-cycloalkyl-A-, C14-haloalkyl-A-, R2.1.1-C14-a1kylene-A-, Ci4-alkyl-A-C14-alkylene-, C3_6-cycloalkyl-A-Ci4-alkylene-, C14-haloalkyl-A-C14-alkylene-, R2.1.1-C14-alkylene-A-C14-alkylene-, R2'-A-C,4-alkylene-, HO-Ci4-alkylene-A-, HO-C14-alkylene-A-C14-alkylene-, C1_4-alkyl-O-C14-alkylene-A- and C14-alkyl-O-C14-alkylene-A-C14-alkylene-; and R2.1.1 is R' and and R2.1.1.a is selected from = aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2.1.1.1;
= C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.1.1;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R21'2; and = C5_10-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1=1.1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.Lt.2;
and R2.1.1.1 i is ndependently selected from halogen, HO-, 0=, C14-alkyl-, C14-alkyl-O-, C1-4-haloalkyl-, C14-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 i is ndependently selected from 0=, C14-alkyl-, C14-haloalkyl-; C3_6-cycloalkyl-, Ci, 4-alkyl-O-C14-alkyl-, H(0)C-, C14-alkyl-(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranyhnethyl; and R2.2 is R2.2.a and R2.2.a is independently selected from H-A-Ci_4-alkylene-, C 1_4 -alkyl-A-C 1_4 C3_6-cyclo alkyl-A-C alkylene-, R2. 1' 1-A-C C LA- S (0),)- and C C (0)-, R2' 11 .
Preferred arc the above compounds of formula 1, wherein R2 is R2'1 and R2-1`
is selected from N N
N
N r,::;) ...N.--and wherein carbon atoms of the ring are optionally and independently from each other substituted with to one, two or three R21, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2; wherein a carbon atom of the ring is optionally substituted with one R2.3 or one R2.5; a nitrogen atom of the ring is optionally substituted with one R2A.
Preferred are the above compounds of formula 1, wherein R2 is R2.1 and R21 is selected from and wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R2.1; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2; wherein a carbon atom of the ring is optionally substituted with one R2.3 or one R2.5; a nitrogen atom of the ring is optionally substituted with one R2A.
Preferred are the above compounds of formula 1, wherein R2 is R2' and R2' is together with R4 and two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S(0), S(0)2, 0 and N, preferably pyrazole, naphtene, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R21, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.2.

Preferred are the above compounds of formula 1, wherein R2 is R2 and R211 is selected from aryl-, pyrazole, thiophene and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R21, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2'2; wherein a carbon atom of the ring is optionally substituted with one R23; a nitrogen atom of the ring is optionally substituted with one R24; or R2' is selected from N
N
N
N
N
H

and I() wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R2.1, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2; wherein a carbon atom of the ring is optionally substituted with one R23 or one R25; a nitrogen atom of the ring is optionally substituted with one R24.
Preferred are the above compounds of formula 1, wherein R2 is R2m and R2m is selected from aryl-, pyrazole, thiophene and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R21; wherein possibly available nitrogen zo atoms of the ring are optionally and independently from each other substituted with R2'2; wherein a carbon atom of the ring is optionally substituted with one R23; a nitrogen atom of the ring is optionally substituted with one R24 .
Preferred are the above compounds of formula 1, wherein R2 is R2'" and RI" is selected from H H H H
H õ....-N.., H H N
fIIII
N kkuorjp_ N N

and , wherein carbon atoms of the ring arc optionally and independently from each other substituted with 5 one, two, three or four R21, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2-2; wherein a carbon atom of the ring is optionally substituted with one R2-3 or one R25; a nitrogen atom of the ring is optionally substituted with one R24.

10 Preferred are the above compounds of formula 1, wherein R2 is R2-q and R2'q is selected from among the substituents (al) to (q1) H
N L HN-Th (al) (bl) (el) 110 HNo [N,._,N,,,- 'N'O
(dl) (el) ..õ.____-Nõ.õ,,,--(l) HN- ,.,, HN)'N`
(gl) N .N,...NH
(h1) (11) H HN HN..¨-------\ N

l) HN NH (11) (j (kl) (ml) (n1) (ol) (IA) (ql) wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R21, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other are substituted with R22;
Particularly preferred R2" is substituent (al) or (cl), wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R21, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other are substituted with R2-2 1() Particularly preferred R2" denotes a substituent selected from the group (al) to (ql), wherein carbon atoms of the ring are optionally and independently from each other substituted with a group selected from among =0, Me, MeS02-, Me-piperazinyl-S02-, morpholinyl, -CN and F, and possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with Me2N-CH2-CH2-, F2CH-CH2-, ¨CH3 and tetrahydrofuranyl.
Preferred are the above compounds of formula 1, wherein R2 is R2's and R2's is Phenyl-R2', wherein the phenyl ring is optionally substituted with one or two residues RI
, wherein R2.1 is R2. I .a and R2'1' is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-C1_4-alkylene-, R2 'LA, C3_6-cycloalkyl-A-, C1_4-haloalkyl-A-, R2.1.1- C 1_4-alkylene-A-, C1_4-alkyl-A-C1_4-alkylene-, C3_ 6-CYClOalkyl-A-C 1_4-alkylene-, C1_4-haloalkyl-A-C]_4-alkylene-, / '1-CX 1_4-alkylene-A-C1_4-alkylene-, HO-C1_4-alkylene-A-, HO-Ci_4-alkylene-A-C14-alkylene-, Ci_4-alky1-0-Ci_4-alkylene-A- and C1_4-alkyl-O-C1_4-alkylene-A-C1_4-alkylene-; and R2.1.1 is R2.1.1.a and RILL .a is selected from = aryl-, optionally substituted independently from each other with one, two or three residues independently selected from RIM;
= C5_10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.1.1;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.12;
= C5_10-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three W.1.1.1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2''2;
and R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_4-alkyl-, C14-alkyl-O-, C1-4-haloalkyl-, C1_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, Cm-haloalkyl-; C3_6-cycloalkyl-, Ct.
4-alkyl-O-C1_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
and R2's and R4 together denote a group (rl), (rl) wherein the N-atom is optionally substituted with ¨122.2, wherein R2.2 is independently selected from H-A-C1_6-alkylene-, C3_8-cycloalkyl-, Ci_6-alkyl-A-C1_6-alkylene-, C3_5-cycloalkyl-A-C1_6-alkylene-, C R2 1=1-A-C1_6-alkylene-, Ci_6-alkyl-S(0)2-, Ci_6-alkyl-C(0)- and R21'-A-.
Particularly preferred are the above compounds of formula 1, wherein R2 is R2's and R2's is Phenyl-R23 , wherein the phenyl ring is optionally substituted with one or two residues independently selected from F and ¨CN , and R2.s and R4 together denote a group (rl ), wherein the N-atom is optionally substituted with ¨
C113, H N
up 0 (r 1).
Particularly preferred are the above compounds of formula 1, wherein R1 is H, is R3 is H or F, preferably F, and R2 is R2 s and R2 s is Phenyl-R23, wherein the phenyl ring is optionally substituted with one or two residues independently selected from F and ¨CN , 20 and R2 s and R4 together denote a group (rl), wherein the N-atom is optionally substituted with ¨CH3;
Particularly preferred are the above compounds of formula 1, wherein R2.s and R4 together denote a group (rl), optionally substituted as described above, in meta and para position of the phenyl ring.
Preferred are the above compounds of formula 1, wherein R2 is R2" and R2' is selected from among the substituents (a2) to (w2) or R2 together with R4 denotes a group selected from among (a3) to (e3).

CH, * *.N
(c2) (a2) (b2) * *
- 0 *--N,r0 *

s- L,N1 / II (e2) 6P-N
0 (d2) 3(f2) N'N'' ''N NO (i2) INo (g2) 1 (h2) *
N '' .l *
) 1\1 N ,y,.....\
N
(12) * '.
(2j) 1--- 0/ 11(2) N 0 'N'' 0 (m2) / F.õ,.
N F
(o2) (n2) /
o r N
)----/
*
'\,------../
(p2) N
(q2) *N
(r2) H
7------- \
l'I\I H
\----. V '>.<0 '''''''N-.

_.,.N.,,,,,,, H 1 (s2) (t2) (u2) (v2) (w2) *

(a3) *
0 (b3) * * *

(c3) (d3) (e3) Particularly preferred R2 r is substituent (a2) or (c2).
Particularly preferred R2 is substituted Phenyl-R23 wherein R2 together with R4 denotes a group selected from among (a3), (b3), (c3), (d3) and (e3).

Preferred arc the above compounds of formula 1, wherein R2.1 is R2=1 a and R2 1 is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-C1A-alkylene-, R2.1.1-A-, C14-alkyl-A-, C36-cycloalkyl-A-, CIA-haloalkyl-A-, R2 1.1-CIA-alkylene-A-, CIA-alkyl-A-CIA-alkylene-, Cs_ 6-eycloalkyl-A-C [4-alkylene-, C14-haloalkyl-A-C14-alkylene-, 10 R2 I-C14-alkylene-A-C14-alkylene-, R2 1-A-C14-alkylene-, HO-C14-alkylene-A-, HO-C1A-alkylene-A-CIA-alkylene-, C1A-alkyl-O-C1A-alkylene-A- and C1A-alkyl-O-C1A-alkylene-A-C1A-alkylene-.
Preferred arc the above compounds of formula 1, wherein R2.11 is R2 1.1' and R2.1.1' is selected from 15 = aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R21'';

= C540-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.1.1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R21.1.2 = and = C540-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1=1=1;
wherein nitrogen atoms of the ring are optionally and independently from each other are substituted with one, two or three R2.1.1.2; and R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_4-alkyl-, C14-alkyl-O-, Ct_ 4-haloalkyl-, C1_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C1_4-alkyl-, C1_4-haloalkyl-; C3_6-eycloalkyl-, C1-4-alkyl-O-C1_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
Preferred are the above compounds of formula 1, wherein R2.1.1 is R2.1.1.b and R2.1.1.b is phenyl or selected from 0 \ __________________________________________________________ N
and N

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R211'1, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2'1.12; and R21.1.1 is independently selected from halogen, HO-, 0=, C14-alkyl-, C1_4-alkyl-0-, C1_ 4-haloalkyl-, C1_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C14-alkyl-, C1_4-haloalkyl-; Ci_ 4-alkyl-O-C1_4-alkyl-, H(0)C-, CL4-alkyl-(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
Preferred are the above compounds of formula 1, wherein R2.1.1 is R2. 1.1.c and is phenyl or selected from 0, and wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three RILL', wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.1.12; and R2'1'1=1 is independently selected from F, Cl, Me, Me0- and cyclopropyl-; and is R2.1.1.2 is independently selected from Me, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
Preferred are the above compounds of formula 1, wherein R2.1.2 is R2.1.2.a and R2.1.2.a is selected from H, NC-, C1_4-alkyl-, C1_4-haloalkyl-, C3_6-cycloalkyl-, HO-C1_4-alkylene- and (C1_ zo 4-alkyl)-0-C1_4-alkylene-.
Preferred are the above compounds of formula 1, wherein R2.1.2 is R2.1.2.b and R2.1.2.b is selected from H, Ci_4-alkyl-, andC3_6-cycloalkyl-;
25 Preferred are the above compounds of formula 1, wherein R2-2 is R2-2.a and R2'2-a is independently selected from H-A-Ci_4-alkylene-, C3_6-cyc1oalkyl-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_ 6"-CYC loalkyl-A-C1_4-alkylene-, C1_4-haloalkyl-A-C1_4-alkylene-, R2.1.1-A-C14-alkylene-, C1_4-alkyl-S(0)2- and C1_4-alkyl-C(0)-, R2.1.1-A-;

Preferred are the above compounds of formula 1, wherein R2.2 is R2.2.b and R22.1) is together with R4 selected from -C(0)-, -S(0)-, -S(0)2-, -C(R11'2)=C(R2'1'2)- and -Cm-alkylene-;
Preferred are the above compounds of formula 1, wherein R23 is together with R4 a group R2'3' and R2.3.a is selected from -0-, - S-, -N(R2'11)-, -C(0)N(R2'3'1)-, -N(R2'3'1)C(0)-, -S(0)2N(R2.3.1)-, -N(R2-3-1)S(0)2-, -C(0) 0-, -0C(0)-, -S(0)-, -S(0)2-, -C(R2'12)=C(R2'3'2)-, -C=N-, -N=C-, -C(R2'12)2-0-, -0-C(R2'3' 2)2_, _c (R2.3.2)2N(R2.3.t)_, _N(R2.3.t)c (R2.3).2,2_ and -C1_4-alkylene-; and R2.3-1 is independently selected from H, Cm-haloalkyl-, HO-C14-alkylene-, (C14-alkyl)-0-C14-alkylene-, H2N-C14-alkylene-, (Cm-alkyl)HN-C14-alkylene- and (C14-alky1)2N-Ct_4-a1kylene-;
R2.3.2 is independently selected from H, Cm-haloalkyl-, C3_6-cycloalkyl-, HO-Cm-alkylene-, (Cm-alkyl)-0-C14-alkylenc-, H2N-C14-alkylene-, (Cm-alkyl)HN-C14-alkylene- and (C14-alky1)2N-C14-alkylene-.
Preferred are the above compounds of formula 1, wherein R24 is together with R4 a group R2'4' and R214' is selected from -N(R2'4'1)-, -C(0)N(R2'4'1)-, -N(R2.4.1)c(0)_, _s(0)2N(R2.4.1)_, _N(R2.4.1)s(-2_, -C(0)-, -S(0)-, -S(0)2-, -C(R24.2)=C(R2.4.2) C=N-, -N=C-, -C(R2'4'2)2N(R2.4.1) N(R2.4.1)c(R2.4)2 .2,and -Cm-alky lene-; and R2A. 1 is independently selected from H, C1_4-haloalkyl-, C3_6-cycloalkyl-, HO-Cm-alkylene-, (Cm-alkyl)-0-Cm-alkylene-, H2N-Cm-alkylene-, (C 14-alkyl)HN-C14-alkylene- and (C14-alky1)2N-C1_4-alkylene-;
R24.2 i is ndependently selected from H, Cm-haloalkyl-, C3_6-cycloalkyl-, HO-C14-alkylene-, (C14-alkyl)-0-C14-alkylene-, H2N-C14-alkylene-, (Cm-alkyl)HN-C14-alkylene-, (C14-alky1)2N-C14-alkylene-.
Preferred arc the above compounds of formula 1, wherein R2'5 is together with R4 a group R2'5" and R2'5'a is selected from -C(R2'5'1)=, =C(R2'5'1)- and -N=; and R2'5=1 is independently selected from H, C
HO-C1_4-alkylene-, (C14-alkyl)-0-C14-alkylene-, H2N-C1_4-alkylene-, (Ci_4-alkyl)HN-Ci..4-alkylene- and (CI4-alky1)2N-C
Preferred are the above compounds of formula 1, wherein R2 is R2-111 and R2' is together with R4 and two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R21, wherein possibly available nitrogen atoms of the ring are optionally and 1() independently from each other substituted with one, two or three R22;
and R2.1 is R2.1.a and R2'1' is selected from H, halogen, NC-, 0=, HO-, H-A-, C3_6-cycloalkyl-A-, C1_4-haloalkyl-A-Cm-alkylene-, R2=11-C14-alkylene-A-C14-alkylene-, HO-Cm-alkylene-A-, HO-Cm-alkylene-A-Cm-alkylene-, C14-alkyl-O-C14-alkylene-A- and C14-alkyl-0-C14-alkylene-A-C14-alkylene-; and R2.1.1 is R2=1''' and R2'1=1' is selected from = aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2-11-1;
= C5_10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1=1'1;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2' .1.2;
= C5_10-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'11=1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1=L2;
and R2.1.1.1 is independently selected from halogen, HO-, 0=, C14-alkyl-O-, C1_ Ci_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, Ci_4-haloalkyl-; C3_6-cycloalkyl-, C1_ 4-alkyl-O-C1_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl- and 5 tetrahydropyranylmethyl; and R2.2 is R2.2.a and R2.2.a is independently selected from H-A-C1_4-alkylene-, C3_6-cycloalky1-A-C1_4ralkylene-, Ci_4-alkyl-S(0)2- and Cl_4-alkyl-C(0)-, Preferred are the above compounds of formula 1, wherein R2 is R2 and R2' is selected from aryl-, pyrazole, thiophene and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R2.1; wherein possibly available nitrogen atoms of the ring arc optionally and independently from each other substituted with R2'2; wherein a carbon atom of the ring is optionally substituted with one R2.3; a nitrogen atom of the ring is optionally substituted with one R2.4; or R2' is selected from N N N
N
kokurjr, (N

,and, zo wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R2.1, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2; wherein a carbon atom of the ring is optionally substituted with one R2-3 or one R25; a nitrogen atom of the ring is optionally substituted with one R2A; and R2.1 is R2. La and R2." is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-C1_4-all(ylene-, R2.1.1-A-, C3_6-cycloalkyl-A-C1_4-alkylene-, Cm-haloalkyl-A-C1_4-alkylene-, R2.1.1-C1_4-alkylene-A-C14-alkylene-, R2.1.1-A-C14-alkylene-, HO-C[4-alkylene-A-C14-alkylene-, C14-alkyl-O-C14-alkylene-A- and C14-alkyl-O-C14-alkylene-A-C14-alkylene-; and R2.1.1 is R2-1-1' and R2-1.1" is selected from = aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2-1-1-1;
= C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.1.1;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2'12; and = C5_10-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)7, 0 and N and the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2-1=1-1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2-1.12;
and R2.1.1.1 is independently selected from halogen, HO-, 0=, C14-alkyl-, C14-alkyl-O-, C1 C14-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C14-alkyl-, C14-haloalkyl-; C3_6-cycloalkyl-, Ct_ 4-alkyl-O-C14-alkyl-, H(0)C-, C14-alkyl-(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R22 is R2 la and R2-2' is independently selected from H-A-C14-alkylene-, C3_6-cycloalkyl-, C14-alkyl-A-C14-alkylene-, C3_6-cycloalkyl-A-C14-alkylene-, Ct4-haloalkyl-A-C14-alkylene-, R2-1-1-A-C14-alkylene-, C14-alkyl-S(0)2- and C4-alkyl-C(0)-, R2-1-1-A-; and R23 is together with R4 a group R2-3-a and R2-3-a is selected from -0-, - S-, -N(R2-3-1)-, -C(0)N(R2-3-i)-, -S(0)2N(R2-3-1)-, -N(R2-3-1)S(0)2-, -C(0)0-, -0C(0)-, -C(0)-, -S(0)-, -S(0)2-, -C(R2-3-2)=C(R2-3-2)-, -C=N-, -N=C-, -C(R2-3.2) 2-0-, -0-C(R2.3.2)2-, -C(R2.3.2)2N(R2-3.1)-, -N(R2.3. I )C(R2.3=2)2- and -C14-all(ylene-; and R2.3.1 is independently selected from H, C1_4-alkyl-, C1_4-haloalkyl-, HO-C1_4-alkylene-, (C1_4-alkyl)-0-C1_4-alkylene-, HN-C1_4-alkylene-, (CIA-alkyl)HN-CIA-alkylene- and (C14-alkyl)N-CiA-alkylene-;
R2.3.2 is independently selected from H, C1_4-alkyl-, C1_4-haloalkyl-, C3_6-cycloalkyl-, HO-C i_4-alkylene-, (Ci_4-alkyl)-0-Ci_4-alkylene-, H,N-C i_4-alkylene-, (C14-alkyl)HN-C1_4-alkylcne- and (C1A-alkyl),N-C1_4-alkylenc-; and is together with R4 a group R2'4' and R2.4.a is selected from -N(R2=4=1)-, -C(0)N(R2=4=1)-, -N(R2.4.1)c(0)_, _s(0)2N(R24.1)_, _N(R2.4.1)s(0)2_, _c(o)_, - S(0)-, -S (0)2-, -C (R2.4.2)=C (R2.4.2) C=N-, -N=C-, -C(R24-2)2N(R2.4.1)_, _N(R2.4. I )c(R2A.2)2 - and -CIA-alkylene-; and R2.4.1 is independently selected from H, C1_4-alkyl-, C1_4-haloalkyl-, C3_6-cycloalkyl-, HO-C1_4-alkylene-, (C14-alkyl)-0-C14-alkylcne-, H7N-C1_4-alkylene-, (C1_4-alkyl)HN-C1_4-alkylene- and (C1_4-alky1)2N-C1_4-alkylene-;
R2.4.2 is independently selected from H, C1_4-haloalkyl-, HO-Ci_4-alkylene-, (C14-alkyl)-0-C14-alkylene-, R2N-C1_4-alkylene-, (C1_4-alkyl)HN-C1_4-allcylene- and (C1_4-alky1)2N-C1_4-alkylene-; and R2-5 is together with R4 a group R2'5' and R2=5' is selected from -C(R2=5=1)=, =C(R2=5=1)- and -N=;
and R2.5.1 is independently selected from H, C1_4-alkyl-, C1_4-haloalkyl-, C3_6-cycloalkyl-, (C14-alkyl)HN-C1_4-alkylene- and (C14-alky1)2N-C1_4-alkylene-.
Preferred are the above compounds of formula 1, wherein RI is RI.b and RI.b is H; or two RI are together -CH2-;
R2 is selected from = R2. I ;
= phenyl-; optionally substituted with one or two residues independently selected from R2-I; optionally substituted with one R23;

= C5-heteroaryl-; containing two or three independently selected from S, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R2.1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R22;
= monocyclic C6-heterocycly1 containing one or two nitrogen atoms, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R2-1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R22; and = bicyclic C9 oi io-freterocycly1-; containing one, two, three or four heteroatoms independently selected from S(0)2, 0 and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R22;
R2.1 is independently selected from halogen, NC-, 0=, H-A-, R2.1.1 A-, C1_4-alkyl-A-, R2'1=1-C1_4-alkylene-A-, andHO-C1_4-alkylene-A-C1_4-alkylene-;
R2.1.1 is independently selected from = phenyl-; and = C5 or 6-heterocycly1-; containing one or two heteroatoms independently selected from 0 and N, wherein the ring is fully or partially saturated, wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one CIA-alkyl-;
R2.2 is independently selected from H-A-C1_4-alkylene-, R2'1=1-A-C14-alkylene- and Ci_4-alkyl-C(0)-;
R23 and R4 are together a group selected from -N(R23'1)-, -C(0)N(R2'32)- and -N(R2'11)C(0)-;
R2.3.1 i is ndependently selected from H and H3C-;
R3 is H or F;

R4 is R4b and R4b is F;
A is a bond or independently selected from -0-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)7N(R5)-, -N(R)S(0)2-, -C(0)0-, -0C(0)-, -C( 0)-, -S(0)2- and -N=(0)(R5)S-;
R5 is independently selected from H and Ci_4-alkyl-;
or a salt thereof 1() Preferred are the above compounds of formula 1, wherein R2 is selected from the Table 1 R2 - Embodiments of the invention for R2, R2.1, R2.1.1, R2.2, R2.3, and R25.
(if present):
E# R2 R2.1 R2.1.1 R/2 R235 .-1 R2' R2.1 R2. 1.1.a -2 R2.a R2.1 R2. 1.1.b -3 R2.a.

R2. 1.1.c -4 R2.b R2.1.a R2.1.1.a -5 R2.b R2. l'a R2.1.1.1) -6 R2.b R2. 1.a R2.1.1.c -7 R2-e R2. 1.a R2. 1.1.a - -8 R2.e Rata R2.1'I.b - -9 R2.e Rate R2. 1.1.c - -R2.c R2. l'a R2. 1.1.c - R2.3.2

11 R2.e Rate R2. 1.1.c - R2. 4.a

12 R2-e R2.1.a R2.1.1.c _ R2. 5.a

13 R2.d R2. 1.a R211' _ -

14 R2.d Rate R2.1.1.b - -R2.d R2. 1.a. R2. 1.1.c - -16 R2.d Rate R2.1.1.c - R2'3.a 17 R2.d R2. I .a R2 .0 .c - R2. 4.a 18 R2.d R2. 1.a R2.1.1.c _ R2. 5.a 19 R2.e R2.1.a R2.1.1.a R222 --E# R2 R2.1 R2.1.1 R2.2 R2.3-5 20 R2.e R2. 1.a R2.1.1.b R2'2.a -21 R2.e R2. 1.a. R2.1.1.c R2.2.a -22 R2s R2 .I a R2. 1.1..a R2.2.a -23 R21 R2. 1.a. R2.1. Lb R2.2.a -24 R2S R4 [a I a " R2.1.1.e R2.2.a -25 RIg R2.1.a R2.1.1.a Ra -26 RIg R2. 1.a. R2.1.1.b R2.2.a -27 R2"g R2.1.a R2. 1.1.e R2.2.5 -28 R2.11 R2. 1.a R2.1.1.a R2.2.a.
-29 R2.h R4 [a I a " R2.1.1.b R2.2.a -30 R2.h. R2. 1.a. R2.1.1.c R2.2.a -31 R2.e R2. 1.a R2.1.1.c - R2.3.a 32 R2.e R2. I.a R2 .1.1"c - R2. 4.a 33 R2.e R2. l'a R2. 1.1.e - R2. 5.a.
34 RIg 9 I a R-- R2.1.1.c - R2.3'a RIg R2. 1.a. R2.1.1.c - R2. µ.1.a.
36 RIg R2. 1.a R2.1.1.c - R2. 5.a 37 R2.h. R2. 1.a R2.1.1.c - R2.3.a 38 R2.h R2- 1.a R2. 1.1.e - R2. ,1.a 39 R2-h R2.1.a R2.1.1 .c - R2. 5.a R2"i R2. 1.a. R2.1.1.a R2.2.a -41 R2"i R2. 1.a R2. 1.1.b R2.2.a -42 R2"i R2. 1.a R2.1.1.c R2.2.a -43 Rli R2. 1.a R2.1.1.a R2.2.a -44 R2-j R2 .1.a R2 1 .h R2.2.a -R2".i R2.1.a R2. I.1.c R2.2.a -46 R2.k R2. 1.a R2.1.12 R2.2.a -47 RIk R2. 1.a R2.1.1.b R2.2.a -48 R2.k R2. 1.a R2.1.1.c R2.2.a -49 R2.I R2 .1.a R2. 1.1.a R2.2.a -R21 R2.1"a R2.1. Lb R2.2.a -51 R21 R2. 1.a R2. I. Le R2.2.a -For a better understanding of the Table 1 R2 - Embodiments of the invention example (E#) 21, can also be read as a group R2, wherein R2 is R2'e and R2'e is C5 or 6- heteroaryl-, containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2'1;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.2; and R2. I
is R2'' and R2-1-a is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-CIA-alkylene-, R2'1=1-A-, C14-alkyl-A-, C3_6-cycloalky1-A-, CIA-haloalkyl-A-, R2.1.1- C14- alkylene-A-, C1A-alkyl-A-C1A-alkylene-, C3_ C1A-haloalkyl-A-C1_4-alkylene-, R2.1.1-C14-alkylene-A-CIA-alkylene-, R2'1=1-A-C14-alky1ene-, HO-C14-alkylene-A-, HO-C14-alkylene-A-C1A-alkylene-, C1A-alkyl-O-C1A-allcylene-A- and CIA-alkyl-O-CIA-alkylene-A-CIA-alkylene-; and R2' I
is R2-' Le and R2- is phenyl or selected from 0 \
N

N
ri and wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2111, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2' 1. 1.2; and R2.1.1.1 is independently selected from F, Cl, Me, Me0- and cyclopropyl-;
and R2.1.1.2 is independently selected from Me, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R22 is 2 2 a R and R22a is independently selected from H-A-C1A-alkylene-, C3_ C1A-alkyl-A-C1A-alkylene-, C3_6-cycloalkyl-A-Ci4-alkylene-, C1A-haloalkyl-A-C1A-alkylene-, Ci4-alkyl-C(0)-, Preferred are the above compounds of formula 1, wherein re is 123" and Ria is H.
Preferred are the above compounds of formula 1, wherein fe is Rib and Rib is F.
Preferred are the above compounds of formula 1, wherein R4 is R4" and R4" is selected from F, Cl, phenyl-H2C-0-, HO-, C14-alkyl-, C1A-haloalkyl-, C3_6-cycloalkyl-, C14-alkyl-0-and CI4-haloalky1-0-.
Preferred are the above compounds of formula 1, wherein R4 is R4'b and R4'b is F; preferably in ortho position.
Preferred are the above compounds of formula 1, wherein A is Aa and Aa is a bond or independently selected from -0-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R5)S(0)2-, -C(0)0-, -0C(0)-, -C(0)-, -S(0 )2-, -(R5)(0)S=N-, -(R5N=)(0)S- and -N=(0)(Ra)S- and R5 is R5" and R5' is independently selected from H, C14-alkyl- and NC-.
Preferred is a compound of formula 1, wherein fe is independently selected from H, C14-alkyl-, halogen, HO-, CI4-alkyl-0-, H2N-, Ci_6-alkyl-HN-, (Ci_6-alky1)2N- and Ci_6-alkyl-C(0)HN-;
or two R1 are together CIA-alkylene;
R2 is selected of the examples of the Table 1 R2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 7, 8, 9, 10, 11, 12, 13, 14,

15, 16, 17, 18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, 41, 42,43,44, 45, 45, 46, 47, 48, 49, 50, 51;

R3 is H or F;
R4 is independently selected from F, Cl, phenyl-H2C-0-, HO-, Ct_6-alkyl-, C3_8-cycloalkyl-, C1_6-haloalky1-0-, (C1_6-alky1)2-HN-, C 1_6-alkyl-HN-CiA-alkylene- and (C1_6-alky02-HN-CI4-alkylene-;
A is a bond or independently selected from -0-, - S-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R5)S(0)2-, -S(0)(=N
R5)-N(10-, -N(R5)(NR5=) ,S(0)-, -S(=NR5)2-N(R5)-, -N(R5)(NR5=)2S-, -C(R5)=C(R5)-, , -C(0)0-, -0C(0)-, -C(0)-, -S(0)-, S(0)2-, -S(=NR5)-, -S(0)(=NT)-, -S(=NR5)2-, -(R5)(0)S=N-, -(R5N=)(0)S- and -N=(0)(R
R5 is independently selected from H, C1_6-alkyl- and NC-;
or a salt thereof.
Preferred is a compound of fonnula 1, wherein is Ri a and Ri a is independently selected from H, CIA-alkyl-, F and HO-.
or two Ri arc together C14-alkylene;
R2 is selected of the examples of the Table 1 R2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, 41, 42,43,44, 45, 45, 46, 47, 48, 49, 50, 51;
R3 iS H or F;
R4 is R4a and R4a is F, Cl, phenyl-H2C-0-, HO-, Cm-alkyl-, C14-haloalkyl-, C3_6-cycloalkyl-, CIA-alkyl-0- and C14-haloalky1-0-;

A is a bond or independently selected from -0-, - S-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R5)S(0)2-, -S(0)(=N
R5)-N(Ra)-, -N(R5)(NR5=) S(0)-, -S(=NR5)2-N(R5)-, -N(R5)(NR5=)2S-, -C(R5)=C(R5)-, , -C(0)0-, -0C(0)-, -C(0)-, S(0)2-, -S(=NR5)-, -S(0)(=N1V)-, -S(=NR5)2-, -(R5)(0)S=N-, -(R5N=)(0)S- and -N=(0)(R
a)S-;
R5 is independently selected from H, CI 6-alkyl- and NC-;
or a salt thereof.
Preferred is a compound of formula 1, wherein R1 is Ri a and R1 is independently selected from H, C4-alkyl-, F and HO-.
or two R1 are together CI 4-alkylene;
R2 is selected of the examples of the Table 1 R2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39 or 43, 44 ,45, 46, 47 and 48;
R3 is H or F;
R4 is R4a and R4a is selected from F, Cl, phenyl-H2C-0-, HO-, C1_4-alkyl-, C1_4-haloalkyl-, C3_ 6-cycloalkyl-, C4-alkyl-O- and C14-baloalky1-0-;
A is A' and A' is a bond or independently selected from -0-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R5)S(0)2-, -C(0)0-, -0C(0)-, -C( 0)-, S(0)2-, -(R5)(0)S=N-, -(R5N=)(0)S- and -N=(0)(R5)S-;
R5 is R5' and R5' is independently selected from H, Ci4-alkyl- and NC-;
or a salt thereof Preferred is a compound of formula 1, wherein R1 is Ri b and R11 is H; or two R1 are together -CH2-;
5 R2 is selected of the examples of the Table 1 R2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39 or 43, 44 ,45, 46, 47 and 48;
R3 is H or F;
10 R4 is R4" and R4" is F;
A is A and A' is a bond or independently selected from -0-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R')S(0)2-, -C(0)0-, -0C(0)-, -C( 0)-, S(0)2-, -(R5)(0)S=N-, -(R5N=)(0)S- and -N=(0)(R5)S-;
R5 is R5' and R5' is independently selected from H, C1_4-alkyl- and NC-;
or a salt thereof.
Preferred is a compound of formula 1, wherein R1 is Ri b and REb is H; or two R1 arc together -CH2-;
R2 is selected of the examples of the Table 1 R2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39 or 43, 44 ,45, 46, 47 and 48;
R3 is H or F;
R4 is R4 b and R4.b is F;
A is A' and A' is a bond or independently selected from -0-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R)S(0)2-, -C(0)0-, -0C(0)-, -C( 0)-, S(0)2-, -(R5)(0)S=N-, -(R5N--)(0)S- and -N=(0)(R5)S-;

R5 is R5' and R5' is independently selected from H, C14-alkyl- and NC-;
or a salt thereof Preferred is a compound of formula 1, wherein R1 is Ri'b and Ri'b is H; or two R1 are together -CF12-;
R2 is selected from = R2.1;
= phenyl-; optionally substituted with one or two residues independently selected from R2.1;
optionally substituted with one R2'3;
= C5-heteroaryl-; containing two or three independently selected from S, 0 and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R2-1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one = monocyclic C6-heterocycly1 containing one or two nitrogen atoms, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R2-1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R2-2; and = bicyclic C9 or io-heterocycly1-; containing one, two, three or four heteroatoms independently selected from S(0)2, 0 and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2-1; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R2.1 is independently selected from halogen, NC-, 0=, H-A-, H-A-C1A-alkylene-, R2.1.1-A-, C3_6-cycloalkyl-A-, R2' l'i-C1_4-alkylene-A-, C 1_4-alkyl-A-C1_4-alkylene-, HO-C1_4-alkylene-A-C1_4-alkylene-; preferably F, NC-, 0=, H-A-, H-A-CH2-, R2.1.1-A-, HC-A-, H3C-CH2-A-, Cyclopropyl-A-, R2'1'1-CH2-CH2-A-, R2-1 H3C-A-CH2-CH2- and HO-C4-alkylene-A-CH2-i is ndependently selected from = phenyl-; and = C5 016-heterocycly1-; containing one or two heteroatoms independently selected from 0 and N, wherein the ring is fully or partially saturated, wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one C14-alkyl-; preferably H3C-;
R2.2 is independently selected from H-A-C1A-alkylene-, C3_6-cycloalkyl-, C1A-alkyl-A-C1A-alkylene-, R2'1=1-A-C14-alkylene-, C1A-alkyl-C(0)-; preferably H-A-CH,-, cyclopropyl-, H3C-A-CH2-CH2-, R2.1.1 -A-CH2-and H3C-C(0)-;
R2.3 and R4 are together a group selected from -N(R2'3'1)-, -C(0)N(R2'3'2)- or R2.3.1 is independently selected from H and H3C-;
is H or F;
R4 is R4b and R4'b is F;
A is a bond or independently selected from -0-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R)S(0)2-, -C(0)0-, -0C(0)-, -C( 0)-, -S(0)2- and -N=(0)(R5)S-;
is independently selected from H or C14-alkyl-;
or a salt thereof.
Preferred are the above compounds of formula 1, wherein R3 is R3a and R3a is H, and R4 is R41" and R4'b is F;
Particularly preferred are the above compounds of formula 1, wherein R3 is H, R4 is F and R2 is R2-q and R2-q is selected from among the substituents (al) to (ql).
Particularly preferred are the above compounds of formula 1, wherein R3 is F and R2 and R4 together denote a group selected from among (rl) to (ti).
Preferably (al) to ((It) or (rl) to (t1) are independently substituted by a substituent selected from among =0, Me, MeS02-, Me-piperazinyl-S02-, morpholinyl, furanyl, Me2N-CH2-CH2-, F2CH-CH2-, -CN
to and F.
Preferred are the compounds of formula I, wherein the compounds are selected from the group consisting of examples 2, 3, 6, 16, 43, 155,193, 249, 250, 254, 283, 284, 322, 323, 324, 325, 326, 328, 329, 330, 331, 333, 342, 343, 351, 352, 353, 354, 355, 356, 357, 358 and 359.
Particularly preferred are the compounds of formula I, wherein the compounds are selected from the group consisting of examples 322, 323, 324, 325 and 326.
Preferred are the above compounds of formula 1, in its enantiomerically pure form of formula 1' (R1)2 H ,/..,-= N
õ.
N

R4 l' wherein RI, R2, 123 and R4 have the above mentioned meaning.
USED TERMS AND DEFINITIONS
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, Ci_6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
In general in single groups like HO, RN, S(0), S(0)2, NC (cyano), HOOC, F1C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C1_4-alkyl-"
means an aryl group which is bound to a Cm-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
Alternatively "*" indicates within a chemical entity the binding site, i.e.
the point of attachment.
In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
Many of the followings terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
The term "substituted" as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
The expressions "prevention", "prophylaxis", "prophylactic treatment" or "preventive treatment"
used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned hereinbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabetes or obesity or another disorder mentioned herein. Thus the expression "prevention of a disease" as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient population without preventive treatment.
The expression "treatment" or "therapy' means therapeutic treatment of patients having already 5 developed one or more of said conditions in manifest, acute or chronic folin, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof. Thus the expression "treatment of a disease" as used herein means the management and care of a patient 10 having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
15 Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc...) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, 20 including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
As used herein the term "prodrug" refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that 25 gives rise to a pharmacologically active metabolite, although not itself active (i.e. an inactive precursor).
The terms "prodrug" or "prodrug derivative" mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some 30 biotransformation prior to exhibiting its pharmacological effect(s).
Such prodrugs either have metabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups. Most common prodrugs include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs:
Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998;
Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T.
Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E.B.
Roche (ed.), Elsevier, 1987.
The term "pharmaceutically acceptable prodrug" as used herein means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2, 2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, Date Recue/Date Received 2020-08-20 hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2, 2', 2"-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2, 5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts,) also comprise a part of the invention.
The term halogen generally denotes fluorine, chlorine, bromine and iodine.

The term "C1,-alkyl", wherein n is an integer selected from 2, 3, 4, 5 or 6, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term Ci.5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH9-CH2-CF2-, H3C-CH2-CH2-CH(CH3)-, fl3C-CH9-CH(CH3)-CF19-, H3C-CH(CH3)-CH2-CH2-, H3C-CF19-C(CF13)2-, H3C-C(CH3)2-CF19-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.
The term "C1,-alkylene" wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term CIA-alkylene includes -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)-C
H2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-, -(CH3)-CH2-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH(CH2CH3)-, -CH(CH2 CH3)-012-, -CH(CH2CH2CF13)- -CH(CH(CH3))2.- and -C(CH3)(CH2CH3)-=
The term "C3,-cycloa1kyl", wherein n is an integer selected from 4, 5, 6, 7 or 8, preferably 4, 5 or 6, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to 8 C atoms. For example the term C3_8-cycloalkyl includes zo cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
By the term "halo" added to a "alkyl", "alkylene" or "cycloalkyl" group (saturated or unsaturated) is such a alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H2FC-, HF2C-, F3C-.
The term "aryl" as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second five- or six-membered, carbocyclic group which may be aromatic, saturated or unsaturated.
Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
The term "C_Io-heterocycly1" means a saturated or unsaturated mono- or polycyclic-ring systems including aromatic ring system containing one or more heteroatoms independently selected from N, 0 or S(0), wherein r = 0, 1 or 2, consisting of 5 to 10 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The term "heterocycly1" is intended to include all the possible isomeric forms. Thus, the term "heterocycly1" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent (single or double) bond to any atom so long as appropriate valences are maintained:
H

H N) 0 \
S N
) /NIEI/NEI )N __ H _____________________________________________________ H S
H
H N H
N H
N
O 0 S .7=N\ -"/3 \ /S
H
H rN ro (N) C) C
) N N

S
( :) 10 ) (0) (s) (s.,, H H

H 0 0 S N7 \C
H
N N H
S __________ S H ) N N
, , N., /'N't\l' NH\c NHc il H

co o o H H H
H H
/N\ /N\ -7N\ /N-, /C) --....õ_../-- -.....õ....-- --....õ.2----- -........õ.õ.--- =-...,,:;:-...---- -..,..._õ-- ...---A) H H H
HH ,..-N,õ ......--N., ,...--N,..õ
N.., N
:_...7 0 ,...-0.., c) S N
O S H
H
N H
0 S > N
N >

H
N
S>
H
is N 0> 0 > > 01 S N

QI
H H

-,, 0 -.., si ,...., / /

N''N' 0-NH 40 s/N HNXNH
The term" C5_10-heteroaryl" means a mono- or polycyclic-ring systems containing one or more 10 heteroatoms independently selected from N, 0 or S(0)r, wherein r = 0, 1 or 2, consisting of 5 to 10 ring atoms wherein at least one of the heteroatoms is part of aromatic ring.
The term "heteroaryl" is intended to include all the possible isomeric forms. Thus, the term "heteroaryl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

H H H
0õ0, Nos N ____ N //k1 /!\ I /7 N\\
/IN
v \\ v __ N \\ / N __ ,N, 0õSõS, S, ...., s.
/71 N N \\ iiN /PI /7 /PI
N NN \==/ NN NN ______________________________ N N N

I +
N N
/pi 1 1 N II 1 ,,, 1 1 -] N
==,>..;,' NN "---N-7. ________ -- -- '` N-4:-. --N
H
N
\ \ N \
/NI
el N N

N N
/ \------.
\\ N
\ \ N ---- \

--.... /
0/ S le N/ N H
NI ------- r'-;N :7',,. N
- `%'--"----"N ''''..--." N 'N-Ki-'-'N - \.%.'----- N ''- -------- /
- H
H N N
H
riN N
`-:.-----N!%-;.---D.--N-----...NY NH N
-....,....
..,..,,,N----, .'.,,.,,,N.--..,1 -.-N--_,,//
H
./i.,,, __ __.---\_,_ ,./7\___,..--,...N N--5-\,..--,-N\ I
NN -,,,,,7-----./
NIN ,_ / N
===,-,,N.---.Nft ' N N.-.) =-=,.,N-...."
H ' '' '"'I/N-----"/
N
/ NI-) N N,N2 -.1\1 ,1\1.-}
=
PREPARATION
GENERAL SYNTHETIC METHODS

The invention also provides processes for making a compound of Formula I. In all methods, unless specified otherwise, RI, R2 and n in the formulas below shall have the meaning of RI, R2 and n in Formula I of the invention described herein above.
Optimal reaction conditions and reaction times may vary dpending on the particular reactants used.
Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC) or LC-MS, if desired, and intermediates and products may be purified by chromatography to on silica gel, HPLC and/or by recrystallization. The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds without undue experimentation. Starting materials and intermediates used, in the methods below, are either commercially available or easily prepared from commercially available materials by those skilled in the art.
A compound of Formula V, VII and IX may be made by the method outlined in Scheme 1:

(R1),, PGHN
OH
X = H, I, Br, N3 No,y(R1), N CN

OH

N
X X X

X = H, I, Br, OTf, N3 III IV V
(R1) X = H, I, Br, OTf, N3 (R1)r, N

VI
PG () X X

X = H, I, Br, OTf, N3 X = H, I, Br, OTf, N3 IX Scheme 1 VIII
As illustrated in Scheme 1, a compound of Formula II, wherein PG represents a protecting group (e.g. tert-butoxycarbonyl), may be reacted with an aqueous ammonia solution, using standard literature procedures for the formation of an amide. For example, in the presence of a base such as N-methyl-morpholine or N-ethyl-morpholine and an activating agent such as 0-(7-Azabenzotriazol-1-y1)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) or 0-(Benzotriazol-1-y1)- N, N, N', N'-tetramethyluroniumtetrafluoroborate (TBTU).
The reaction is conveniently carried out in a suitable solvent such as N, N-dimethylformamide.
Standard peptide to coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) may be employed in these syntheses.
Dehydration of an amide such as in a compound of Formula III or Formula IX to the corresponding nitrile of Formula IV or VII may be carried out by use of a dehydration agent such as (methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, in a suitable solvent such as dichloromethane (DCM).
Reacting an acid of Formula VI using standard literature procedures for the formation of an amide, for example in the presence of a base such as N, N-diisopropylethylamine (DIPEA) and an activating agent such as HATU or TBTU, with an amine of Formula V or VIII in a suitable solvent, provides a compound of Formula VII or IX. Standard peptide coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) may be employed in these syntheses.
The protection and deprotection of functional groups is described in 'Protective Groups in Organic Synthesis', T. W. Greene and P. G. M. Wuts, Wiley-Interscience. For example, for the deprotection of tert-butoxycarbonyl, an acid such as formic acid, trifluoroacetic acid, p-toluenesulfonic acid or HC1 may be used in a suitable solvent such as water, DCM or dioxanc. Another method to deprotect tert-butoxycarbonyl is the reaction with trimethyliodosilane or trimethylchlorosilane in combination with sodium iodide in an appropriate solvent like acetonitrile, DMF or DCM.

(R1), NCJ,Ii_H
N CN (R1),, PG 0 01 ,Tr,H
N CN
B(OR)2 H

/ Vila R4 R3 \

(R1)r, (R1), NOyH N
CN ,tiN CN
N
-E.

X
X = I, Br, OTf or N3 X

(R1), (R1)n OrrH y H
N N

_m...
X = I, Br, OTf or N3 X R2 \ (Ri)n /

Cr\-,.irH
N

B(OR)2 IXa R3 Scheme 2 During the reaction sequences depicted in Scheme 1 and Scheme 2 a hydroxy group (X=OH ) can be converted to a trifluoromethanesulfonyl group (X=0Tf) at any level.
Especially, a compound IX
5 with X=OH is transformed to the appropriate triflate (X=011) by reaction with N,N-bis-(trifluoromethanesulfonyl) aniline, or trifluoromethanesulfonyl chloride or anhydride, in the presence of an organic base e.g. triethylamine, morpholine, piperidine, DIPEA
in an appropriate anhydrous solvent, e.g. DCM.

As illustrated in Scheme 2, (transition) metal catalyzed reaction of a compound of Formula VII or IX wherein Xis I,Br, Cl or OTf, provides a compound of Formula X or XI. For example, reaction with a boronic acid or the corresponding boronic acid ester, in a suitable solvent such as acetonitrile, in the presence of a suitable catalyst such as 1, 1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a suitable base such as K2CO3 provides a compound of Formula X or XI.
Alternatively, reaction of a compound of Formula VII or IX, wherein X is I, Br, Cl or OTf with a tributyl(vinyl)tin reagent in the presence of a suitable catalyst such as bis-(triphenylphosphin)-palladiumchlotide, in a suitable solvent such as dimethylformamide (DMF) and if desireable in the presence of an additive such as tetraethylammonium chloride provides compounds of Formula X or XL Further, reaction of a compound of Formula VII or IX, wherein X is I or Br, may be reacted with an amine in the presence of a suitable catalyst such as Cu(I)I and a suitable base such as caesium carbonate and a suitable promotor such as L-proline provides a compound of Formula X
or XI.
In an inversed fashion compounds of formula VII or IX (X: T, Br, Cl, OTf) can be converted into the corresponding boronic acid derivatives Vila or IXa, wherein R can be H or lower alkyl independently and the residues R can form a ring. For example, VII or IX can be reacted with bis-pinacolato-diboron in the presence of a suitable catalyst such as 1, 1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a suitable base such as potassium acetate or sodium, potassium or cesium carbonate or phosphate, in a suitable solvent such as dioxan, dimethylformamide (DMF), or dichloromethane (DCM) to yield the boronic esters Vila or IXa, respectively. These can be reacted with appropriate aromatic halides in analogy as above to yield the desired coupling products of formula X or XI.
Further, as illustrated in Scheme 2, reaction of a compound of Formula VII or IX, wherein X is N3 with an alkyne in the presence of a suitable catalyst such as copper(II)sulfate pentahydrate and a suitable reducing agent such as L-ascorbic acid in a suitable solvent such as dimethyl sulfoxide (DMSO) / water provides a compound of Formula X or XI.
Further modifications of compounds of Formula X, XI and I by methods known in the art and illustrated in the Examples below, may be used to prepare additional compounds of the invention.

Dehydration of an amide of Formula XI to the corresponding nitrile of Formula X may be carried out by use of a dehydration agent such as (methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, in a suitable solvent such as DCM.
(1:21), (R1)2OH, PG PG
HN CN HN CN PG 0 ICI\%11.1rH
CN
VI

X R2 _no.

iv XII
X = I, Br, CI, OTf or N3 Scheme 3 As illustrated in Scheme 3, (transition) metal catalyzed reaction of a compound of Formula IV
wherein X is I, Br, Cl or OTf, provides a compound of Formula XII. For example, reaction with a m boronic acid or the corresponding boronic acid ester, in a suitable solvent such as acetonitrile, in the presence of a suitable catalyst such as 1, 1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a suitable base such as K2C01 provides a compound of Formula XII.
An acid of Formula VI using standard literature procedures for the formation of an amide, for example in the presence of a base such as DIPEA and an activating agent such as HATU or TBTU, can be reacted with an amine of Formula XII in a suitable solvent. Standard peptide coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) may be employed in these syntheses. Deprotection of functional groups is described in 'Protective Groups in Organic Synthesis', T. W. Greene and P. G. M. Wuts, Wiley-Interscience. For example, for the deprotection of tert-butoxycarbonyl, an acid such as formic acid, p-toluenesulfonic acid, trifluoroacetic acid or HCl may be used in a suitable solvent such as water, DCM or dioxane and can be performed on the crude amide coupling product to provide a compound of Formula I. Another method to deprotect tert-butoxycarbonyl is the reaction with trimethyliodosilane or trimethylchlorosilane in combination with sodium iodide in an appropriate solvent like acetonitrile, DMF or DCM.

N

Y=CI, Br, OSO2R R2 XIII V
XIV
Scheme 4 As illustrated in Scheme 4, amino nitrile derivatives of Formula XIII can be converted to substituted amino nitriles of Formula V via alkylation to compounds of Formula XIV, followed by deprotection of the amino group. During the alkylation step a suitable base is used in an appropriate solvent, using a benzylation agent XV with an appropriate leaving group like Cl, Br, or sulfonates.
Especially useful is the use of sodium hydroxide as base in water and DCM
under phase transfer conditions using benzyltrimethylammonium chloride as described for example by Naidu et al, W02011/46873. The protective group is removed under acidic conditions, e.g.
aq. HC1 in dioxan.
The amino nitrile V is further processed as depicted in Scheme 1.

(R1) (R1)n ,õ , N UN UN N
0 ________________________ s .

0¨

(R1)n (R1)n \
Ciir H õ c_i_r H
N L,IN N CN
pG* H

..¨

R

XVIII X = I, Br, CI, OTf XVII x= I, Br, CI, OTf R5 \ (R1)^
Orr (Ri)n H,,õ, UN
N 0 PG*

PG 0 N,PG* +
XIXb R3 R5 R3 XIXa /
i (R1) (R1), L:j_.,Irr H ,,,, UN, H C N

H H
o N 0 XXb R3 XXa R3 Scheme 5 As illustrated in Scheme 5, nitro compounds of foimula XV can be reduced to anilines of formula XVI by catalytic hydrogenation under conditions, where the nitrile group is still stable. Better suited are reagents like sodium dithionite, SnC12 or iron in a suitable solvent like water, methanol, ethanol, acetonitrile or ethyl acetate.

Reacting of 2-halo-benzoic acid, especially 2-iodo-benzoic acid using standard literature procedures for the formation of an amide, for example in the presence of a base such as N, N-diisopropylethylamine (DIPEA) and an activating agent such as HATU or TBTU, with an amine of 5 Formula XVI in a suitable solvent, provides a compound of Formula XVII.
Standard peptide coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) may be employed in these syntheses.
The benzoic amide group as in Formula XVII can be protected by an acid labile group, especially 10 by alkoxymethyl or silylalkoxymethyl groups as mentioned for example in 'Protective Groups in Organic Synthesis', T. W. Greene and P. G. M. Wuts, Wiley-Interscience.
Especially useful is the use of 2-trimethylsilylethoxymethylchloride as alkylating agent after having removed the amide proton by a strong base such as NaH in an inert solvent like DMF, THF or dioxan. The products are compounds of the formula XVIII.
Cyclisation of compounds like formula XVITT can be performed with the aid of a palladium catalyst like Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0) and a base like potassium acetate or sodium, potassium or cesium carbonate or phosphate, especially sodium carbonate in a suitable solvent, e.g. DMF, preferrably under elevated temperature. This results in the formation of .. compound of the formula XIXa and XIXb, which can be separated or processed further as a mixture.
Compounds like XIXa or XIXb or a mixture thereof can be deprotected in acidic medium.
Deprotection of functional groups is described in 'Protective Groups in Organic Synthesis', T. W.
Greene and P. G. M. Wuts, Wiley-lnterscience. For example, an acid such as formic acid, p-toluenesulfonic acid, trifluoroacetic acid or HC1 may be used in a suitable solvent such as water, DCM or dioxane and can be performed on the crude amide coupling product to provide a compound of Formula XXa and XXb. Another method to deprotect first the tert-butoxycarbonyl is the reaction with trimethyliodosilane or trimethylchlorosilane in combination with sodium iodide in an appropriate solvent like acetonitrile, DMF or DCM. After that the trimethylsilylmethoxymethyl group can be removed in acidic medium as mentioned above, especially with formic acid again leading to compounds of the formula XXa and XXb.

SYNTHETIC EXAMPLES
The following are representative compounds of the invention which can be made by the general synthetic schemes, the examples, and known methods in the art. Starting materials and intermediates were either commercially availableand purchased from catalogues of AATPHARM, ABCR, ACROS, ACTIVATE, ALDRICH, ALFA, ALLICHEM, ANICHEM, ANISYN, ANISYN
Inc., APAC, APOLLO, APOLLO-INTER, ARKPHARM, ARKPHARMINC, ASIBA PHARMATECH, ATOMOLE, BACHEM, BEPHARM, BIOFOCUS, B1OGENE, BORON-MOL, BOROPHARM, CHEMBR1DGE, CHEMCOLLECT, CHEMFUTURE, CHEMGENX, CHEMIMPEX, CHESS, COMBI-BLOCKS, COMBI-PHOS, DLCHIRAL, EGA, E-MERCK, EMKA-CHEMIE, ENAMINE, EPSILON, FLROCHEM, FLUKA, FOCUS, FRONTIER, ISOCHEM, JW PHARMLAB, KINGSTONCHEM, LANCASTER, MANCHESTER, MANCHESTER ORGANICS, MAYBRIDGE, MAYBR-INT, MERCACHEM, MERCK, MILESTONE, MOLBRIDGE, NETCHEM, OAKWOOD, PHARMABRIDGE, PLATTE, RIEDEL DE HAEN, SMALL-MOL, SPECS, SPECTRA GROUP
LIMITED, INC, SYNCHEM OHG, SYNCHEM-INC, SYNCOM, TCT, VIJAYA PHARMA, WAKO, WUXIAPPTEC or were synthesized according to literature or as described below in "Synthesis of starting materials/ educts"
"Liquid chromatography-mass spectroscopy (LCMS) retention time and observed rn/z data for the compounds below are obtained by one of the following methods:
LC-MS Method 001_CA07 Device-Description Waters Acquity with DAD and MSD
Column Waters Sunfire C18 Column Dimension 2.1 x 50mm Particle Size 2.5 um Gradient/Solvent /0 Sol {H2O 0.1% % Sol [Acetonitrile 0.08% Flow [ml/min]
Temp [ C]
Time [mm] TFA] TFA]
0.0 95.0 5.0 1.5 60.0 0.75 0.0 100.0 1.5 60.0 0.85 0.0 100.0 1.5 60.0 LC-MS Method 002_CA03 Device-Description Agilent 1100 with DAD and MSD
Column Waters Sunfire C18 Column Dimension 3.0 x 30mnn Particle Size 2.5 um Gradient/Solvent % Sol [H2O 0.1% TFA] % Sol [Acetonitrile Flow [ml/min]
Temp [ C]
Time [min]

0.0 99.0 1.0 2.0 60.0 0.9 0.0 100.0 2.0 60.0 1.1 0.0 100.0 2.0 60.0 LC-MS Method 002_CA07 Device-Description Waters Acquity with 3100 MS
Column Waters XBridge BEH C18 Column Dimension 3.0 x 30mm Particle Size 1.7 gm Gradient/Solvent % Sol [H20 0.1% NH4OH] % Sol [Acetonitrile Flow [ml/min] Temp [ C]
Time [min]
0.0 95.0 5.0 1.5 60.0 0.7 0.1 99.9 1.5 60.0 0.8 0.1 99.9 1.5 60.0 0.81 95.0 5.0 1.5 60.0 1.1 95.0 5.0 1.5 60.0 LC-MS Method 003_CA04 Device-Description Agilent 1100 with DAD and MSD
Column Waters XBridge C18 Column Dimension 3.0 x 30mm Particle Size 2.5 gm Gradient/Solvent% Sol [H20 0.1% NH4OH] A Sol [Acetonitrile Flow [ml/mm]
Temp [ C]
Time [min]
0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0 LC-MS Method 004_CA01 Device-Description Agilent 1100 with DAD, Waters Autosampler and MSD
Column Waters Sunfire C18 Column Dimension 4.6 x 30mm Particle Size 3.5 gm Gradient/Solvent/0 Sol [H20 0.1% % Sol Flow [ml/min] Temp [ C]
Time [min] TFA] [Acetonitrile]
0.0 98.0 2.0 2.5 60.0 1.5 0.0 100.0 2.5 60.0 1.8 0.0 100.0 2.5 60.0 LC-MS Method 004_CA05 Device-Description Waters Acquity with DAD and MSD, CTC
Autosampler Column Waters XBridge C18 Column Dimension 3.0 x 30mm Particle Size 2.5 gm Gradient/Solvent% Sol [H20 0.1% A) Sol Flow [ml/min] Temp [ C]
Time [min] NH4OH] [Acetonitrile]
0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0 LC-MS Method 004_CA07 Device-Description Waters Acquity with with 3100 MS
Column YMC Triart 018 Column Dimension 2.0 x 30 mm Particle Size 1.9 j.tm Gradient/Solvent% Sol [H20 0.1 /aNH4OH]% Sol [AcetonitrileFlow [ml/min]
Temp [ C]
Time [min]
0.0 95.0 5.0 1.5 60.0 0.75 0.1 99.9 1.5 60.0 0.8 0.1 99.9 1.5 60.0 0.81 95.0 5.0 1.5 60.0 1.1 95.0 5.0 1.5 60.0 LC-MS Method 005_CA01 Device-Description Agilent 1100 with DAD , Waters Autosampler and MS-Detector Column Waters Sunfire 018 Column Dimension 3.0 x 30nnnn Particle Size 2.5 !um Gradient/Solvent% Sol [H20 % Sol Flow [ml/min] Temp [ C]
Time [min] 0.1% TFA] [Acetonitrile 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0 LC-MS Method V001_003 Device-Description Waters Alliance with DAD and MSD
Column Waters XBridge C18 Column Dimension 4.6 x 30 mm Particle Size 3.5 lam Gradient/Solvent % Sol % Sol [Methanol] Flow [ml/min] Temp [ C]
Time [min] [H20,0.1%TFA]
0.0 95 5 4 60 0.20 95 5 4 60 1.5 0 100 4 60 1.75 0 100 4 60 LC-MS Method V001_007 Device-Description Waters Alliance with DAD and MSD
Column Waters XBridge C18 Column Dimension 4.6 x 30 mm Particle Size 3.5 p.m Gradient/Solvent % Sol % Sol [Methanol] Flow [ml/min] Temp [ C]
Time [min] [H20,0.1%TFA]
0.0 95 5 4 60 1.6 0 100 4 60 1.85 0 100 4 60 1.9 95 5 4 60 LC-MS Method V003_003 Device-Description Waters Alliance with DAD and MSD
Column Waters XBridge C18 Column Dimension 4.6 x 30 mm Particle Size 3.5 [tin Gradient/Solvent % Sol [H20, 0.1% NH3] % Sol [Methanol] Flow [ml/min] Temp [ C]
Time [min]
0.0 95 5 4 60 0.2 95 5 4 60 1.5 0 100 4 60 1.75 0 100 4 60 LC-MS Method VO11_SO1 Device-Description Waters Alliance with DAD and MSD
Column Waters XBridge C18 Column Dimension 4.6 x 30 mm Particle Size 3.5 i.tm Solvent Gradient time % Sol [H20, 0.1% % Sol Flow [ml/min] Temp [ C]
[min] NH3] [Acetonitril]
0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60 LC-MS Method V012_SO1 Device-Description Waters Alliance with DAD and MSD
Column Waters XBridge C18 Column Dimension 4.6 x 30 mm Particle Size 3.5 !nu Solvent Gradient time 1)/0 Sol % Sol Flow [ml/min] Temp [ C]
[min] [H20,0.1%TFA][Acetonitril]
0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60 LC-MS Method V018_SO1 Device-Description Waters Alliance with DAD and MSD
Column Waters Sunfire C18 Column Dimension 4.6 x 30 mm Particle Size 3.5 p.m Solvent Gradient time % Sol % Sol Flow [ml/min] Temp [ C]
[min] [H20,0.1%TFA][Acetonitril]
0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60 LC-MS Method W018_SO1 Device-Description Waters 1525 with DAD and MSD
Column Waters Sunfire C18 Column Dimension 4.6 x 30 mm Particle Size 2.5 Jim Solvent Gradient time [min] % Sol % Sol [Acetonitril] Flow [ml/min] Temp [ C]
[H20Ø1c/oTFA]
0.0 97 3 4 60 0.15 97 3 3 60 2.15 0 100 3 60 2.20 0 100 4,5 60 2.40 0 100 4,5 60 5 LC-MS Method X001_002 Device-Description Waters Acquity with DAD and MSD
Column Waters Xthidge BEH C18 Column Dimension 2.1 x 30 mm Particle Size 1.7 jim Gradient/Solvent A Sol % Sol [Methanol] Flow [ml/min] Temp [ C]
Time [min] [H20,0.10%TFA]
0.0 99 1 1.3 60 0.05 99 1 1.3 60 1.05 0 100 1.3 60 1.2 0 100 1.3 60 LC-MS Method X001_004 Device-Description Waters Acquity with DAD and MSD
Column Waters Xthidge C18 Column Dimension 2.1 x 20 mm Particle Size 2.5 Rim GradientiSolvent % Sol % Sol [Methanol] Flow [ml/min] Temp [ C]
Time [min] [H20,0.10 /0TFA]
0.0 95 5 1.4 60 0.05 95 5 1.4 60 Device-Description Waters Acquity with DAD and MSD
1.00 0 100 1.4 60 1.1 0 100 1.4 60 LC-MS Method X002_002 Device-Description Waters Acquity with DAD and MSD
Column Waters Sunfire C18 Column Dimension 2.1 x 30 mm Particle Size 2.5 um Gradient/Solvent % Sol A Sol [Methanol] Flow [ml/min] Temp [ C]
Time [min] [H20,0.10%TFA]
0.00 99 1 1.2 60 0.15 99 1 1.2 60 1.10 0 100 1.2 60 1.25 0 100 1.2 60 LC-MS Method X011_SO2 Device-Description Waters Acquity with DAD and MSD
Column Waters XBridge BEH 018 Column Dimension 2.1 x 30 mm Particle Size 1.7 pm Solvent Gradient % Sol ')/0 Sol [Acetonitril] Flow [ml/mm]
Temp [0C]
time [H20,0.1"YoNH3]
[min]
0,00 99 1 1,3 60 0,02 99 1 1,3 60 1,00 0 100 1,3 60 1,10 0 100 1.3 60 LC-MS Method X011_SO3 Device-Description Waters Acquity with DAD and MSD
Column Waters Xbridge BEH 018 Column Dimension 2.1 x 30 mm Particle Size 1.7 pm Solvent Gradient `)/0 Sol % Sol [Acetonitril] Flow [ml/min]
Temp [0C]
time [H20,0.1cYoNH3]
[min]
0,00 95 5 1,3 60 0,02 95 5 1,3 60 1,00 0 100 1,3 60 1,10 0 100 1,3 60 LC-MS Method X012_SO1 Device-Description Waters Acquity with DAD and MSD
Column Waters XBridge Column Dimension 2.1 x 30 mm Particle Size 1.7 gm Solvent Gradient time % Sol A Sol Flow [mlimin] Temp [ C]
[min] [H20,0.1%TFA] [Acetonitril]
0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60 LC-MS Method X012_S02 Device-Description Waters Acquity with DAD and MSD
Column Waters XBridge BEH 018 Column Dimension 2.1 x 30 mm Particle Size 1.7 pm Solvent Gradient % Sol % Sol [Acetonitril] Flow [ml/min]
Temp r01 time [H20, 0.1% TFA]
[min]
0.0 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60 LC-MS Method X016_SO1 Device-Description Waters Acquity with DAD and MSD
Column Waters XBridge BEH Phenyl Column Dimension 2.1 x 30 mm Particle Size 1.7 gm Solvent Gradient time % Sol % Sol Flow [ml/min] Temp [ C]
[min] [H20,0.1`)/0TFA][Acetonitril]
0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60 LC-MS Method X018_SO1 Device-Description Waters Acquity with DAD and MSD
Column Waters Sunfire C18 Column Dimension 2.1 x 30 mm Particle Size 2.5 gm Gradient/Solvent % Sol `)/0 Sol [Acetonitril] Flow [ml/min] Temp [ C]
Time [min] [H20,0.1 /0TFA]
0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0 100 1.5 60 1.10 0 100 1.5 60 LC-MS Method X018_S02 Device-Description Waters Acquity with DAD and MSD
Column Waters Sunfire C18 Column Dimension 2.1 x 30 mm Particle Size 2.5 gm Gradient/Solvent ')/0 Sol % Sol [Acetonitril] Flow [ml/min] Temp [ C]
Time [min] [H20,0.1 /0TFA]
0.0 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60 LC-MS Method Z001_002 Device-Description Agilent 1200 with DAD and MSD
Column Waters XBridge C18 Column Dimension 3 x 30 mm Particle Size 2.5 gm Gradient/Solvent % Sol ')/0 Sol [Methanol] Flow [mlimin] Temp [ C]
Time [min] [H20,0.1%TFA]
0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.80 0 100 2.2 60 LC-MS Method ZO11_SO3 Device-Description Agilent 1200 with DAD and MSD
Column Waters XBridge C18 Column Dimension 3 x 30 mm Particle Size 2.5 gm Gradient/Solvent% Sol % Sol [Acetonitril] Flow [ml/min] Temp [ C]
Ti me [m in] [H20,0.1`)/oNH3]
0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 LC-MS Method Z011_1103 Device-Description Agilent 1200 with DAD and MSD
Column Waters XBridge C18 Column Dimension 3 x 30 mm Particle Size 2.5 gm Gradient/Solvent% Sol % Sol [Acetonitril] Flow [ml/min] Temp [ C]
Time [min] [H20,0.11)/0NH3]
0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 '0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 LC-MS Method Z012_SO4 Device-Description Agilent 1200 with DAD and MSD
Column Waters XBridge C18 Column Dimension 3 x 30 mm Particle Size 2.5 gm Gradient/Solvent% Sol % Sol [Acetonitril] Flow [ml/min] Temp [ C]
Time [min] [H20,0.1%NH3]
0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 LC-MS Method Z018_SO4 Device-Description Agilent 1200 with DAD and MSD
Column Waters Sunfire C18 Column Dimension 3 x 30 mm Particle Size 2.5 gm Solvent Gradient time [min] % Sol % Sol [Acetonitril] Flow [ml/min] Temp [ C]
[H20,0.1%TFA]
0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 LC-MS Method ZO2O_SO1 Device-Description Agilent 1200 with DAD and MSD
Column Waters Sunfire C18 Column Dimension 3 x 30 mm Particle Size 2.5 gm Solvent Gradient time [mm] % Sol % Sol [Acetonitril] Flow [ml/min] Temp [ C]
[H20,0.1%FA]
0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 LC-MS Method V001_007 Device-Description Waters Alliance with DA- and MS-Detector Column XBridge C18 Column Dimension 4.6 x 30 mm Particle Size 3.5 pm Solvent Gradient time % Sol % Sol Flow [ml/min] Temp [ C]
[min] [H20,0.1%FA][Methanol]
0.0 95 5 4.0 60 1.6 0 100 4.0 60 1.85 0 100 4.0 60 1.9 95 5 4.0 60 LC-MS Method I_ADH_15_MEOH_DEA.M
Device-Description Agilent 1260 SFC with DAD
Column Daicel Chiralpak AD-H
Column Dimension 4.6 x 250 mm Particle Size 5 gm Solvent % Sol % Sol Flow [ml/min] Temp [ C]
Backpressure Gradient time [scCO2] [Methanol, [bar]
[min] 0.2%
Diethylamine]
0.00 85 15 4 40 150 10.00 85 15 4 40 150 LC-MS Method I_OJI-1_10_IPROP_DEA.M
Device-Description Agilent 1260 SFC with DAD
Column Daicel Chiralcel OJ-H
Column Dimension 4.6 x 250 mm Particle Size 5 gm I
Solvent % Sol % Sol Elow [ml/min] Temp [ C] Backpressure Gradient time [scCO2] [Isopropanol, [bar]
[min] 0.2%
Diethylamine]
0.00 90 10 4 40 150 10.00 90 10 4 40 150 LC-MS Method I_IC_20_MEOH_NH3.M
Device-Description Agilent 1260 SFC with DAD and MSD
Column Daicel Chiralpak IC
Column Dimension 4.6 x 250 mm Particle Size 5 p.m Solvent % Sol /0 Sol Flow [ml/min] Temp [ C] Backpressure Gradient time [scCO2] 20mM NH3 in [bar]
[min] lethanol]
0.00 80 0 4 40 150 10.00 80 0 4 40 150 LC-MS Method I_ADI1_40_MEOH_DEA.M
Device-Description ' gilent 1260 SFC with DAD
Column ID aicel Chiralpak AD-H
Column Dimension 4.6 x 250 mm Particle Size = gm Solvent % Sol % Sol I low [ml/min] Temp [ C] Backpressurc Gradient time [scCO2] [Methanol, [bar]
[min] 0.2%
Diethylamine]
0.00 60 40 , 40 150 10.00 60 40 , 40 150 LC-MS Method I_ASH_30_10MIN_SS4P.M

Device-Description Berger SFC Analytix with DAD
Column Daicel Chiralpak AS-H
Column Dimension 4.6 x 250 mm Particle Size 5 gm Solvent Sol ,/0 Sol Flow [ml/min] Temp [ C] Backpressure Gradient time [scCO2] [Ethanol, 0.2% [bar]
[min] Diethylamine]
0.00 70 30 4 40 120 10.00 70 30 4 40 120 LC-MS Method I_OJH_10_MEOH_DEA.M
Device-Description Agilent 1260 SFC with DAD
Column Daicel Chiralcel OJ-H
Column Dimension 4.6 x 250 mm Particle Size 5 lam Solvent % Sol % Sol Flow [ml/min] Temp [ C] Backpressure Gradient time [scCO2] [Methanol, [bar]
[min] 0.2%
Diethylamine]
0.00 90 10 4 40 150 10.00 90 10 4 40 150 Mixture of stereoisomers can be separated on preparative scale by one of the following chiral SFC
methods. 2x describes two columns switched in a row.
Methode: Chiral SFC A
Column: 2x Daicel Chiralpak AD-H 5 m 20x250mm Eluent: 85% scCO2, 15% Methanol 0.2% Diethylamine to Flow: 55mL/min Temperature: 40 C
Backpressure: 120bar Wavelength: 254nm Concentration: 52mg/m1 in Methanol Injection volume: .. 300R1 Device-Description: Thar MultiGram 11 Methode: Chiral SFC B
Column: 2x Chiralcel OJ-H 5 ,m, 20x250mm Eluent: 90% scCO2, 10% Isopropanol 0.2% Diethylamine Flow: 60mL/min Temperature: 40 C
Backpressure: 150 bar Wavelength: 254nm Concentration: 50mg/m1 in Methanol Injection volume: 200p1 Device-Description: Jasco Rockclaw 150 Methode: Chiral SFC C
Column: 2xDaicel Chiralpak AD-H 5itm, 10x250mm Eluent: 85% scCO2, 15% Methanol 0.2% Diethylamine Flow: 10mL/min Temperature: 40 C
Backpressure: 120 bar Wavelength: 254nm Concentration: 15mg/m1 in Methanol Injection volume: 100111 Device-Description: Thar MiniGram Methode: Chiral SFC D
Column: lx Daicel Chiralpak AD-H, 5 um, 20x250mm Eluent: 60% scCO2, 40% Methanol 0,2% Diethylamine Flow: 60mL/min Temperature: 40 C
Backpressure: 120 bar Wavelength: 254 nm Concentration: 50mg/m1 in Methanol Injection volume: 400111 Device-Description: Thar MultiGram II

Methode: Chiral SFC E
Column: 2x Daicel Chiralpak AS-H 5 um, 20x250mm Eluent: 70% CO2, 30% Ethanol 0,2% Diethylamine Flow: 55irriL/min Temperature: 40 C
Backpressure: 120 bar Wavelength: 254 nm Concentration: 100mg/m1 in Methanol to Injection volume: 2000 Device-Description: Thar MultiGram II
Methode: Chiral SFC F
Column: Daicel Chiralpak IC 5ittm, 20x250mm Eluent: 85% scCO2, 15% Ethanol Flow: 60mL/min Temperature: 40 C
Backpressure: 150 bar Wavelength: 254 nm Concentration: 35mg/m1 in Methanol Injection volume: 5000 Device-Description: Sepiatec Prep SFC 100 Methode: Chiral SFC G
Column: Chiralpak AY-10 m, 50x300mm Eluent: A for CO,), and B for ethanol: n-heptane = 1:1 Gradient: B 10%
Flow: 170mL/min Temperature: 38 C
Backpressure: 100 bar Wavelength: 220 nm Concentration: 300mg/m1 in ethanol Injection volume: 4mL per injection Cycletime: 3.5 min Device-Description: Thar 200 preparative SFC

Synthesis Methods:
Method A
10 Synthesis of (1S,25,4R)-N-[(1S)-1-cyano-2-[2-fluoro-442-methylisoindolin-5-yliphenyliethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 1) o \ 0 E NH, R2 Br r 1-1.1 N

N
N
0 Br R4 411 1-1.3 LN

1-1.2 T 0 0 H CC\
R5 y_o F
1-1.4 1-1.5 Example 1 Step 1: Synthesis of Intermediate I-1.1 RI (20.0 g, 55 mmol) is suspended in DCM (400 mL) and a solution of R2 (26.4 g, 111 mmol) dissolved in DCM is added. The reaction mixture is stirred for 12 h under argon atmosphere. The reaction mixture is washed with water. The organic layer is dried over MgSO4, filtrated and concentrated. The residue is dissolved in DCM, filtrated by flash chromatography (using solvent mixture cyclohexanel ethyl acetate = 70/30) and concentrated to give I-1.1.
Yield 97% m/z 287/343 [M+H]+, rt 1.29 min, LC-MS Method X012_S01.
The following intermediate as shown in Table 2 is synthesized in a similar fashion from the appropriate intermediates:
Table 2 Intermediate Educt Structure m/z [M+H]+ rt (min) LC-MS method H õANI
Y
R1.1 0 - 391 1.29 V012_S01 Step 2: Synthesis of Intermediate 1-1.2 To I-1.1 (5.80 g, 17 mmol) in anhydrous dioxanc (60 mL) R3 (5.20 g, 20 mmol) and potassium acetate (4.98 g, 51 mmol) are added. The mixture is purged with argon, [1, l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdC12(dppf)) (1.38 g, 1.7 mmol) is added to the mixture and heated to 80 C for 2 h. DCM is added and the mixture is filtrated. The filtrate is diluted with water and extracted with DCM. The organic layer is dried over MgSO4, filtrated and concentrated. The residue is purified by flash chromatography (cyclohexane/
ethyl acetate = 8/2) and concentrated. Yield 97% rez 291/335/391 [M+H]+, rt 1.36 min, LC-MS Method V012 _S01.
Step 3: Synthesis of Intermediate 1-1.3 1-1.2 (1.22 g, 5 mmol) and R4 (2.30 g, 5.9 mmol) arc dissolved in acetonitrile (25 mL). Na2CO3-solution (2 mol/L, 4.9 mL) and 1,1'-Bis(di-tert-butylphosphino)ferrocene-palladium dichloride (319 mg, 0.49 mmol) are added. The reaction mixture is stirred at 80 C for 1 h.
The crude mixture is extracted with ethyl acetate, washed with half saturated brine. The organic layer is dried over MgSO4, filtrated and concentrated and the residue is purified by reversed phase HPLC. Yield 59%, nilz = 396 [M+H]+, rt 0.96 mm, LC-MS Method V012_S01.
The following intermediates as shown in Table 3 are synthesized in a similar fashion from the appropriate intermediates:
Table 3 m/z LC-MS
Intermediate Educt Structureof Intermediate rt (min) [M+H]+ method y 0 I-1.1.1, 0 _N
direct coupling I-1.3.1 444 1.21 V018SO1 with _ boronic ester R7.3 // S 02 M e N

1-1.3.2 1-1.2 446 1.18 V012 SO1 .0 N '0 H -N
direct _ o =
coupling 1-1.3.3 444 1.14 V011 SO1 with boronic SO2Me ester R7.1 Step 4: Synthesis of Intermediate 1-1.4 1-1.3 (1.15g, 2.91mmol) is dissolved in acetonitrile. 1.39 g p-toluenesulfonic acid monohydrate is added and stirred for 48 h. The precipitate is filtered off, dissolved in ethyl acetate and washed with saturated NaHCO3-solution. The organic layer is dried over MgSO4, filtrated and concentrated.
Yield 78%. m/z 296 [M+H]+, rt 1.03 min, LC-MS Method VO1 l_S01.
The following intermediates as shown in Table 4 are synthesized in a similar fashion from the appropriate intermediates:
1,) Table 4 m/z LC-MS
Intermediate Educt Structure of Intermediate rt (min) [M+H]+ method 1-1.4.1 1-1.3.1 FDI 344 0.76 V018 SO2Me I I
1-1.4.2 1-1.3.2 F 346 0.96 V011 Szzo 1-1.4.3 1-1.3.3 344 0.77 V018 N
SO2Me Step 5: Synthesis of Intermediate 1-1.5 To R5 (purchased from Aldrich or synthesized in analogy to Tararov et al, Tetrahedron Asymmetry 13 (2002), 25-28) (98 mg, 0.4 mmol) in DMF (1.5 mL) diisopropylethylamine (0.18 mL, 1.0 mmol) and HATU (154 mg, 0.4 mmol) are added and the reaction mixture is stirred for 15 min.
Then intermediate 1-1.4 (100 mg, 0.3 mmol) is added and the mixture is stirred for 12 h. DCM is added and the mixture is washed with saturated Na2CO3 solution. The organic layer is dried over MgSO4, filtrated, and the residue is concentrated. Then the residue is purified by reversed phase HPLC. Yield 68%, m/z 419/463/518 [M+H]+, rt 1.29 min, LC-MS Method VO1 1_S01.
The following intermediates as shown in Table 5 are synthesized in a similar fashion from the appropriate intermediates:
Table 5 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (mm) method H

1-1.5.1 1-1.4.1 567 1.24 V018 S01 SO2Me 1-1.5.2 1-1.4.2 569 1.24 VOl1_SO1 ,0 /e> H
Nr-yN

1-1.5.3 1-1.4.3 0 567 1.14 VO11_SO1 N
SO2Me Step 6: Synthesis of Example 1 To 1-1.5 (120 mg, 0.23 mmol) in acetonitrilc, p-tolucnesulfonic acid monohydrate (110 mg, 0.58 mmol) is added and stirred for 3 d. The reaction solution is purified by reversed phase HPLC. Yield 5 47%, m/z 419 [M+H]+, rt 1.16 min, LC-MS Method V011_501.
Method Al Synthesis of (1S,2S,4R)-N-1(1S)-1-cyano-2-[2-fluoro-4-(1-methyl-2-oxo-indolin-10 yl)phenyllethyl]-3-azabicyclo[2.2.11heptane-2-carboxamide (Example 2) OH \ 0 1 0/1\1 NH2 R5 Ch< NH, R2 0 Br Br Br 1-2.1 1-2.2 r N 401 B-0 H \JF H
N/
/ R7 eL0 0, 1-2.3 Example 2 Step 1: Synthesis of Intermediate I-2.1 To R5 (7.59 g, 31 mmol) in DCM (300 mL) diisopropylethylamine (4.8 mL, 28 mmol) and HATU
(11.5 g, 30 mmol) are added and stirred for 25 min. Then R6 (10.4 g, 28 mmol) and diisopropylethylamine (7.2 mL, 42 mmol) are added and stirred for 3 h. The solvent is evaporated, dissolved in ethyl acetate and washed with water, 0.5 M HC1 and aq. NaHCO3 solution (10%). The organic layer is dried over MgSO4, filtrated and concentrated. The residue is purified by flash chromatography (using solvent mixture DCM/ methanol = 95/5). Yield >95%, m/z 484 [M+H]+, rt io 1.18 min, LC-MS Method VO1 l_S01.
The following intermediates as shown in Table 6 are synthesized in a similar fashion from the appropriate intermediate:
is Table 6 miz rt LC-MS
Intermediate Structure [M+H]+ (min) method miz rt LC-MS
Intermediate Structure [M+H]+ (min) method ) H
1-2.1.1 NH, 496 0.95 Z018 SO4 4(11N,0 Br , Br 1-2.1.2 484/486 0.71 X018 SO2 F

1-2.1.3 0 - 440 0.55 Z011 S03 OH
Step 2: Synthesis of Intermediate 1-2.2 To I-2.1 (12.7 g, 26 mmol) in DCM (130 mL) R2 (12.5 g, 52 mmol) is added. The reaction mixture is stirred for 12 h. The solvent is evaporated, dissolved in ethyl acetate and washed with water, 0.1 M HC1 and aq. NaHCO3 solution (5%). The organic layer is dried over MgSO4 and concentrated.
The residue is recrystallized from DCM and acetonitrile. Yield 64% rn/z 466 [M+H]+, rt 1.30 min, LC-MS Method V011_S01.
The following intermediates as shown in Table 7 are synthesized in a similar fashion from the appropriate intermediate:
Table 7 Intermediate Educt Structure of Intermediate m/z rt LC-MS

[M+H]+ (min) method N
N
1-2.2.1 1-2.1.1 478 1.03 Z018 SO4 it(1111\1)yLO
o Br H
y el Br 1-2.2.3 1-2.1.2 466/468 1.27 V011 SO1 F
Synthesis of Intermediate 1-2.2.2 Synthesis of tcrt-butyl (1S,2S,4R)-2-[[(1S)-2-amino-14[2,3-difluoro-4-trifluoromethylsulfonyl oxy)phenyl]methy1]-2-oxo-ethyl]carbamoy1]-3-azabicyclo[2.2.1]heptane-3-carboxylate 0 o o 0 NH, NH, OH IH
1-2.1.3 0 r 1-2.2.2 The phenol 1-2.1.3 is transformed into the corresponding trifluoromethanesulfonate 1-2.2.2: 1.2.1.3 m .. (200 mg, 0.46 mmol) is dissolved in anhydrous DCM (1.5 mL). Triethylamine (95 L, 0.69 mmol) is added and the reaction mixture is cooled to 0 C. R18 (179 mg, 0.50 mmol) is then added and the mixture was stirred at 0 C for 90 minutes and additional 12 h at room temperature. The mixture is concentrated and the residue is purified by reversed phase HPLC. Yield 85%, m/z 472 [M+H-BOC]+, rt 0.97 min, LC-MS Method ZOI 1_S03.
Step 3: Synthesis of Intermediate 1-2.3 To 1-2.2 (5.00 g, 10 mmol) in acetonitrile (100 mL) R7 (3.07 g, 11 mmol) is added. The mixture is purged with argon, 1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.70 g, 1.1 mmol) and aq. sodium carbonate solution (2 mol/L, 1.07 mL) are added and the mixture is heated to 70 C for 3,5 h. Ethyl acetate and water are added to the reaction mixture.
The organic layer is washed with aq. NaHCO3 solution (5%) and water. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography (cyclohexanef ethyl acetate = 1/1).
Yield 41% m/z 533 [M+H]+, rt 1.25 min, LC-MS Method VO11_S01.
The following intermediates as shown in Table 8 arc synthesized in a similar fashion from the .. appropriate intermediates ((R, S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 8 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 1-2.3.1 1-2.2 o/-c):11 560 0.76 X018 SO1 A¨CH, ,0 H3C cH3 (-14 -..3 CH, 0.
0 j S
1-2.3.2 1-2.2 (61 = , 41# 528 0.88 004 CA01 )<CH:

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method S
0 j/ / z VI\ H
1-2.2 \r0 470 0.90 004 CA05 0\___CH, N .3 H
1-2.2 \r 0 510 0.87 004_CA05 )s.....CH3 1-2.2 VI% 482 0.77 004_CA05 X¨CH3 0 V j/
0 CH3 i H
1-2.2 468 0.92 004 CA05 X¨ CH3 H3C cH3 1\;1>jiircH
N
1-2.3.7 1-2.2 o oo N 454 0.82 ZO11S03 H3CiCH3 F _ NH

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method N
0 j/
CH, VI\V
1-2.3.8 1-2.2 Nr 0 496 0.82 004 CA05 0CH, H3L CH, F F

1-2.3.9 1-2.2 Ltr: H 538 1.00 004 X¨ CH3 0 j/
1-2.3.10 1-2.2 \r- 0 470 0.91 004 CA05 N
VI:
1-2.3.11 1-2.2 539 0.66 004_CA05 X¨ CH3 H30 CH, N

(N- CH
C(r.j I\N cH3 1-2.3.12 1-2.2 \r. 0 482 0.75 004 CA05 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H N
44;(1:LN.y.%
1-2.3.13 Y = 2.2.1 407 1.03 Z018 SO4 r-CH, I =N
_cNCH3 V
N 1 1\11 1-2.3.14 1-2.2 499 0.86 004_CA05 CH, H3C CH, NF
/*0 438 1-2.3.15 1-2.2 0 [M+H- 0.94 X018_SO4 N
BOC]+
H3C cH3 0 j/ \N
1-2.3.16 1-2.2 552 0.77 004 CA05 /*cp )\--H3C cHCH33 1-2.3.17 I-2.2 0/.0 556 0.91 X018 SO4 s "3,_, cH3 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method N¨ N
0 jI
1-2.3.18 1-2.2 \ro 518 0.89 004 CA05 CH, oil N

1-2.3.19 1-2.2 CH 482 0.77 004_CA05 X¨ CH3 - N [13C
N
1-2.3.20 1-2.2 510 0.86 004 CA05 H3C CH, - N

.N N. CH3 1-2.3.21 1-2.2 CH, 482 0.75 004_CA01 0. CH3 n' CH3 ¨N

Ns...(CH3 Itri CH, 1-2.3.22 1-2.2 496 0.82 004_CA01 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method I
_N

N NH
V-41) 1-2.3.23 1-2.2O 554 0.68 004_CA05 cIxN
o 1-2.3.24 IE 530 1.02 Z018 SO4 2.2.1 H3C,14.0cH3 CH

/N
VI:J4 CH3 1-2.3.25 1-2.2 512 0.83 004_CA01 nCH
CH3, 1-2.3.26 1-2.2 Ny H 3 354 1.02 Z018 SO4 3 rCH

Vi\yA
1-2.3.27 1-2.2 530 0.91 004_CA01 n-CH, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method CH, S¨( N

1-2.3.28 1-2.2 499 0.82 004 CA05 X¨CH, NF

LN
1-2.3.29 1-2.2 [M+H- 1.02 Z018_SO4 X¨ 0H3 BOC]+
H3C CH, H
1-2.3.30 1-2.2 H,C CH3 560 0.76 X018 SO1 )\--- .0 cH3 Vi\lj 1-2.3.31 1-2.2 CH, 468 0.9 004 CA01 n'CH

H
<TNTJAN./
Y =
1-2.3.32 H3C 0 397 0.97 Z018 SO4 2.2.1 rat F
S--1(N
CH, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method L 1-2.3.33 1-2.2 0 0, 431 1.07 Z018 SO4 X¨ CH, \ IN

H3q o N N
, N
1-2.3.34 1-2.2 I 512 0.75 004 CA01 H30 CH, F F
F
N
1-2.3.35 1-2.2 N H ' CH3 536 0.89 004 .0 F

\--CH, H3C CH, N ,V

VI\ //
N
1-2.3.36 1-2.2 0 F 454 0.85 004 CA01 N H
N
VIµ11 CH3 1-2.3.37 1-2.2 \r 1 F 468 0.69 004 CA01 0 CH, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method L
1-2.3.38 1-2.2 CH, 482 0.78 004_CA01 H3C CH, Ny0 1-2.3.39 411 1.01 Z018 SO4 2.2.1 H3c.ocH

eLH fO
1-2.3.40 1-2.2 354 0.87 Z018 SO4 NH
0 JI \ 0 Crj1 OH
1-2.3.41 1-2.2 514 0.44 004 CA05 )\-0H3 H3C CH, 0 // _N
1-2.3.42 1-2.2 538 0.76 004 CA01 H3C CH, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method N

1-2.3.43 1-2.2 o o 483 0.93 V012_SO1 H3C+HCH3 N,CH3 0 I\N
1-2.3.44 1-2.2 F F
536 0.85 004 CA05 X-CH, H,C CH3 V
I-2.3.45 1-2.2 H3C
483 0.81 004_CA05 N-N

VI\N CH3 1-2.3.46 1-2.2 482 0.77 004_CA05 H3C CH, N, 0 CH, 1-2.3.47 .4<eN
2.2.1 547 0.83 004 CA05 \-CH3 H3C CH, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 1-2.3.48 519 0.71 004 CA05 2.2.1 r0 0),CH, H,C CH3 NH
0 ii 2.2.1 1-2.3.49 533 0.77 004_CA05 .4(1-yL N
N r 0 or CH3 H3c CH, 1-2.3.50 '' 519 0.89 004_CA05 2.2.1 \r0 0 CH, 540 0.9 004 CA05 1-2.3.51 2.2.1 .41(eN ' )ç- CH3 H,C CH, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method NH
I I

1-2.3.52 531 0.74 004 CA05 2.2.1 ..clieL HN

)ç- CH
H,C CH, N-CH

I I

1-2.3.53 -.<111\FIN 530 0.81 004 CA05 2.2.1 X¨CH3 H3C CH, 9.NH
= 2 S'0 0 >
1-2.3.54 =
N 555 0.72 004 CA05 2.2.1 <CrA'N H
\r0 0)s_CH3 H3c CH, N-CH
I I

1-2.3.55 530 0.85 004 CA05 2.2.1 <ell X¨ CH, H,C CH, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method I \N

1-2.3.56 494 0.79 004 CA05 2.2.1 IreLH
\r0 0NrCH3 Y1.13 N

1-2.3.57 N "
569 0.71 004 CA05 2.2.1 Nr0 0s....CH3 NH

569 0.66 004 CA05 1-2.3.58 2.2.1 )ç- CH3 H3C CH, so 1-2.3.59 N 554 0.79 004 CA05 2.2.1 AliteL'H
r0 0)s.--CH3 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 1-2.3.60 502 0.81 004 CA05 2.2.1 4:::CeLHN

\-CH3 ji 1-2.3.61 555 0.74 004 CA05 <INI LN
2.2.1 H
(PO
X-CH
H3C CH,-, s,.CH3 1-2.3.62 554 0.79 004 CA05 2.2.1 CI

1-2.3.63 511 0.87 004 CA05 2.2.1 \-CH3 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 2.2.1 0 =NH2 .4(eLN-) 519 0.73 004 CA05 1-2.3.64 \r0 0)s_CH, o 1-2.3.65 531 0.71 004 CA05 2.2.1 .4(e N

\-CH, H3C CH, NH

I I
1-2.3.66 545 0.74 004 CA05 2.2.1 N

X- CH, .CH, 1-2.3.67 jI
545 0,76 004 CA05 _ 2.2.1 <tr)L N ''''"

\-CH3 H3C CH, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method HN.CH3 1,0 S:

1-2.3.68 569 0,79 004_CA05 2.2.1 <(NN

X¨ CH, 1-2.3.69 .47(triAN " 568 0,82 004 CA05 2.2.1 \r0 1-2.3.70 1-2.2 [M+H- 0.97 X018_SO4 \¨CH, H3C CH3 BOC]+
H3C--;s, 0- '0 H
NyO
i F

1-2.3.71 1-2.2 H3C 0 [M+H- 1.00 X018_SO4 r---- CH3 CH3 BOC]+
0=s=0 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method N
CCI\cµly_L 0 r 2--1-2.3.72 1-2.2 577 n.d. n.d.

1-CH, CH, H N
- F
ey'L 0 z 1-2.3.73 1-2.2 561 n.d. n.d.

CH, 1-2.3.74 o o 469 0.89 Z018 SO4 2.2.2 'jH 0 '141111\LN)(NH, 1-2.3.75 0 0 578 0.88 Z018 SO4 2.2.2 0 SO2Me H
1\14tri\IN, -NH2 455 .L 1-2.3.76 0 0 o (M+H- 0.85 Z018_SO4 2.2.2 BOC)+

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H

1-2.3.77 (M+H- 0.89 Z018_SO4 2.2.2 N BOC) ;:jti 0 .NtrIl-Y'A NH2 503 1-2.3.78 o o (M+H- 0.89 Z018 SO4 2.2.2IIIIL SO2Me BOC)+
N
HN
1-2.3.79 1-2.2 00 626 0.54 X012 0=1=0 ( 1-2.3.80 1-2.2 N,r0 T11(M+H- 0.89 Z018 SO4 ..õ
BOC)+
c?-0H
H ,N
N

,N
1-2.3.81 1-2.2 [M+H- 0.89 n.d.
T:7> BOC]+
HO

nitt z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method o 1-2.3.82 1-2.2 508 0.94 Z018 SO4 -<?.-1-- -'Z,-----,H,----,-,-., I
--,õ(-----, O OH
Nõ.........õ4-1-1-2.3.83 1-2.2 ......--s,...
F / n.d. n.d. n.d.
N

During the synthesis of intermediates 1-2.3.17 and 1-2.3.29 the bromide (1-2.2) is transformed into the corresponding dioxaborolane compound. Coupling with aromatic bromides is performed in analogy to the synthesis of intermediate 1-1.3 (method A).
Intermediate 1-2.3.43 is further processed via hydrogenation before the BOC
group is removed (step 4) H õ N
-, ' 0 ,-,k, =
0, 0 0 0 )\-- F / )\---- F
N N
1-2.3.43 1-2.3.43.1 to To 1-2.3.43 (90 mg, 0.19 mmol) in methanol (10 mL) Pd/C (10%, 20 mg) is added. The reaction mixture is stirred under hydrogen (50 psi) for 3 h. Then the mixture is filtered and concentrated.
The crude product is carried on with step 4. Yield >95%

In analogy the following intermediates as shown in Table 9 are prepared.
Table 9 m/z rt LC-MS
Intermediate educt Structure [M+H]+ (min) method H

o o 1-2.3.43.2 517 0.47. X012_S02 3.2.78 H C4 CH
3 CH, 3 1 1-2.3.43.3 00 561 n.d. n.d.
2.3.83 H3C I CH, F
N
CH3 ' Intermediates I-2.3.74-78 and 1-2.3.43.2 are converted to the corresponding nibiles in analogy to step 2 of method Al to yield the compounds in the following Table 10.
Table 10 miz rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H õN

1-2.3.74.1 1-2.3.74 o'o 1 [M+H- 0.98 Z018 S01 I
BOC]+
F

1-2.3.75.1 1-2.3.75 I (M+H+)- 0.96 Z018_SO4 BOC
SO2Me miz rt __ LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method I-2.3.76.1 1-2.3.76 o'4o z (M+H- 0.93 Z018_SO4 H
F BOC)+

F
IjI IrAN

.4 0 ii,h 1-2.3.77.1 1-2.3.77 IWI , (M+H- 0.96 Z018 SO4 /\.. F I N
F N BOC)+
\--CO
tIN 485 .4 ' 1-2.3.78.1 1-2.3.78 o o 0 (M+H- 0.96 Z018_SO4 /-\ F SO2Me BOC)+
F
' N

1-2.3.43.2.1 0 0 499 0.54 X012_SO2 2.3.43.2 õ.õ....---...õ
F
I
The intermediate 1-2.3.7 is combined with appropriate halogcnides or acid chlorides before (in step 4) the BOC group is removed Br 0 R17 /
===., A
F
NH ....õ--- . ........
F
N
---.. /
N
1-2.3.7 1-2.3.7.1 To 1-2.3.7 (45 mg, 0.10 mmol) and R17 (19 .1.1_,, 0.20 mmol) in DMF (1.5 mL) potassium carbonate (42 mg, 0.30 mmol) is added. The reaction mixture is heated to 80 C for 12 h.
The mixture is purified directly by reversed phase HPLC. Yield 65%, m/z 526 [M+H]+, rt 0.71 min, LC-MS
Method X018_S01.
The following intermediates as shown in Table 11 are synthesized in a similar fashion from the appropriate intermediates:
io Table 11 m/z rt LC-MS
Intermediate educt Structure of Intermediate [M+H]+ (min) method 1-2.3.7.3 0 0 496 0.77 X018_SO1 2.3.7 H,CiCH, F CH3 ,N-µ

?)...ii ,k. 1-2.3.7.4 I- 0 0 0 538 0.72 X018 SOI
2.3.7 H3CHCH3 F ---N
-- , N')-0 1-2.3.7.5 I- ,L 0 0 0 .
552 0.79 X018 SO1 2.3.7 H3CiCI-13 F --..._ ) I

m/z rt LC-MS
Intermediate cduct Structure of Intermediate [M+H]+ (min) method N
Er\t/r E

1-2.3.7.6 0 0 512 0.72 X018 S01 23.7 H3 C4'CH3 F

---. ,N-\
cH3 i\tlir 1[1 ."N 438 1-2.3.7.7 0 0 [M+H- 1,11 X018 S01 2.3.7 II I CH, _ H3CiCH, F
----- N4 (CH3 BOC]+

I.j1 N

i _ I-1-2.3.7.8 2.3.7 H3 CCH3 F --- 593 0.69 X018 SO1 CH3 NK_ N---... , N
¨CH3 1,;1>J-11--Eicl'YX;-N
I- .,L 1 1-2.3.7.9 0 0 0 ) 566 0.79 X018SO1 2.3.7 _.... , 1 H3CiCH, FN _ 1-2.3.7.10 o 0 0 526 0.75 X018_SO1 2.3.7 H3CiCH3 F
-- N¨ 'CH, m/z rt LC-MS
Intermediate cduct Structure of Intermediate [M+H]+ (min) method HN

494(M+H-1-2.3.7.11 0 0 1.03 2.3.7 )\-7 F- BOC)+

The reaction conditions for 1-2.3.7.11 differ: Pyridine and dichlormethane instead of potassium carbonate and DMF is used.
Intermediate 1-2.3.7.4 is separated according to method chiral SEC B to give the following intermediates as shown in Table 11.1 Table 11.1 m/z rt Intermediate Educt Structure of Intermediate [M H] LC-MS method (min) o o o I OJH 10 IPROP DE
1-2.3.7.4.1 2.3.7. n.d. 3.90 CH, H C'kCH, F A.M -1-2.3.7.4.2 2.3.7. n.d. 3.4 0<( A.M

.0 Step 4: Synthesis of Example 2 To 1-2.3 (2.35 g, 4.4 mmol) in acetonitrile (50 mL) sodium iodide (1.98 g, 13 mmol) and chlorotrimethylsilane (1.44 g, 13 mmol) are added. The mixture is stirred for 111, then methanol is added, stirred for additional 30 min and then concentrated. The residue is purified by reversed phase HPLC. Yield 47%, m/z 433 [M+H]+, rt 0.59 min, LC-MS Method X011_S01.
Method A2.1 Synthesis of (1S,25,4R)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxo-3H-isobenzofuran-yl)phenyl]ethyl]-3-azabicyclo12.2.1]heptane-2-carboxamide (Example 3) o 0 o_ _ Br 1-2.1 1-3.1 Br R8 >j1 1-3.2 0 04 0 r / NA¨ +

__________________ 0 0 1-3.3 0 Example 3 Step 1: Synthesis of Intermediate 1-3.1 To 1-2.1 (1.00 g, 2.1 mmol) in dioxane (5 mL) R3 (0.58 g, 2.3 mmol) is added.
The mixture is purged with argon. [1,1r-Bis(diphenylphosphino)ferrocene]dichloropalladium(11) as a complex with dichloromethane (34 mg, 0.04 mmol) and potassium acetate (0.39 g, 3.9 mmol) are added. The mixture is heated to 100 C for 12 h. Water is added to the reaction mixture, which is extracted with diethyl ether. The organic layer is washed with brine, dried over MgSO4, filtrated and concentrated.
Yield 74% in/z 532 [M+H]+
The following intermediates as shown in Table 12a are synthesized in a similar fashion from the appropriate intermediate:
Table 12a Intermediate Educt Structure of Intermediate m/z rt LC-MS
[M+H]+ (min) method 1-3.1.1 0- '0 V011 SO
1-2.2 A_ F Br 514 0.90 i , , 1 - F
:

SO
- 1-3.1.2 1-2.2 0 _...
432 1.05 V H ......-N1 ,1 _....--i,Ny -r- F
H....._0 E
1-3.1.3 1-2.2 514 0.95 ZO1l_SO3 ,0 OZ-_.<k, 0 V011 SO
1-3.1.5 1.2.1 0 0 (Borona 0.67 ....0 1 F cid) During the synthesis of intermediate 1-3.1.2 , 1-3.1.4 and 1-3.1.5 instead of R3 5,5,5',5'-Tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] is used.
During the synthesis of intettnidiate 1-3.1 1-3.1.2 and 1-3.1.4 also the corresponding boronic acid is isolated as shown in Table 12b. Either the boronic ester or boronic acid is used for the next steps.
Table 12b Intermediate Educt Structure of Intermediate m/z rt LC-MS
[M+H]+ (min) method H

1-3.1.4 1-2.2.3 N 0 432 0.88 F - B, 1 OH
H

1-2.1 X016 SO
1-3.1.6 0 449 0.42 OH

N
- F

1-3.1.7 1.2.2 H 432 0.56 X018 SO

0 )0 Step 2: Synthesis of Intermediate 1-3.2 To 1-3.1 (295 mg, 0.66 mmol, as boronic acid (1-3.1.6)) in acetonitrile (4 mL) aq. Na2CO3-solution (2 M, 663 L) is added. The mixture is purged with argon, R8 (154 mg, 0.72 mmol) and [1,1'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) as a complex with dichloromethane (80 mg, 0.10 mmol) are added. The reaction is stirred at 70 C for 4 h. Ethyl acetate is added and the mixture is filtrated. The filtrate is washed with water and aq. Na2CO3 solution (10%). The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography (DCM/ methanol = 97/3). Yield 53%.
The following intermediates as shown in Table 13 arc synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 13 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method o N"-VijL NH

1-3.2.1 1-3.1 .4 0 E
0 0 551 1.08 V011_SOI

H N
N

1-3.2.2 520 1.21 V011_SOI
eµlpi H
N
1-3.2.5 1-3.1 --k-0--40 0 0 n.d. n.d. n.d.

eH p41 No y_ -F
1-3.2.6 (1S)-I-3.1.1 447/491/547 1.18 VO1 1 SO1 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H o 1-3.2.8 I-3.1 o =
0 o n.d. n.d. n.d.

H N
õ F
1-3.2.10 (1S)-I-3.1.1 NO 0 519 1.11 VO1 1 SO1 0.1 NH
H N
N
1-3.2.11 1-3.1.1 00 0 n.d. n.d. n.d.
/-\
H N
N

1-3.2.12 I-3.1.1 0 o n.d. n.d. n.d.
N
I
CI
N
N
1-3.2.13 I-3.1.1 0 0 o n.d. n.d. n.d.
N,N CI

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method o N'A NH2 1-3.2.15 1-3.1 0 0 n.d. n.d. n.d.
1\1Th N).' NH2 1-3.2.16 1-3.1 o 0 n.d. n.d. n.d.

N. jt N, NH2 o 1-3.2.17 1-3.1 o o n.d. n.d. n.d.
F
H
c368 (M+H-1-3.2.36 1-3.1.3 ut, BOC)+ _ - 0.73 004 1-3.2.36 .1\1¨

H
F
1-3.2.37 1-3.1.3 NO 382 (M+H-0.75 004_CA05 BOC)+

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H
Ct*NrC) F
415 (M+H-1-3.2.38 1-3.1.3 0.95 004 CA05 BOC)+

Nyp 430(M+H-1-3.2.39 1-3.1.3 0.91 004 CA05 BOC)+
N

H
efLO F
405 (M+H-1-3.2.40 1-3.1.3 0.74 004 CA05 BOC)+
_\) \N-O
NOF 405 (M+H-1-3.2.41 1-3.1.3 0.67 004 CA05 BOC)+
N N

r-rH N
N
F
NO 405 (M+H-1-3.2.42 1-3.1.3 0 0.77 004 CA05 BOC)+
NN
11_ m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method ,>NF
1-3.2.43 1-3.1.3 NO ^ N 382 (M+H-0.72 004 CA05 BOC)+

H N
N

394 (M+H-1-3.2.44 1-3.1.3 ,.,42 BOC)+ 0.70 004 CA05 ^ N

NO 411 (M+H-1-3.2.45 1-3.1.3 0.88 004 CA05 BOC)+
S A

1-3.2.46 1-3.1.3 NO 397 (M+H-0.68 004 CA05 0 BOC)+
/

NO
379 (M+H-1-3.2.47 I-3.1.3 0.85 004 CA05 0 BOC)+
=N
NF
1-3.2.48 1-3.1.3 NO _ 442 (M+H-0.92 004 CA05 ¨ 0 BOC)+
/p m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H
_ 442 (M+H-1-3.2.49 I-3.1.3 0.94 004 CA05 0 BOC)+

H õN
1-3.2.50 1-3.1.3 412 (M+H-0.84 004 CA05 - 0 0 BOC)+

H õN
1-3.2.51 1-3.1.3 611 n.d. n.d.

LH
N,r0 1-3.2.52 1-3.1.3 613 1.24 V012 SO1 H ,>N
ITIN)yLO F
1-3.2.53 1-3.1.3 466 (M+H-0.91 Z018 SO4 ftj BOC)+
IN

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H
N ' N

1-3.2.54 1-3.1.3 o 647 n.d. n.d.
f\L ,ON
1-3.2.55 1-3.1.2 568 1.23 V011 SO1 !!
NO F
H ,N
"F

1-3.2.56 1-3.1.2 622 1.24 VO1 1 SO1 H

N
N
1-3.2.57 1-3.1.2 547 0.76 X011 SO3 N H

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H N
N

[
1-3.2.58 1-3.1.2 494 0.57 X011 SO3 H
N N F
1-3.2.59 1-3.1.2 o< 494 0.56 X011 SO3 N

,.1;,.1i;
F
Lt NO
I
1-3.2.60 1-3.1.2 552 0.58 X011 S03 I
If 10 H
N
N 0 Fl 380(M+H-1-3.2.61 1-3.1.2 0.52 X011 S03 BOC)+

, 1-3.2.62 1-3.1.2 380(M+H-0.52 X011 SO3 BOC)+
, m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H
F
N,r0 I 455(M+H-1-3.2.63 1-3.1.3 - 2 0.93 Z018 SO4 LI BOC)+

H N
1-3.2.64 1-3.1.3 538 0.94 Z018 SO4 o 1) ,N
N. ,0 466(M+H-1-3.2.65 1-3.1.3 D. N 0.91 Z018 SO4 ( BOC)+
N
0'1 r), fl F

525(M+H-1-3.2.66 1-3.1.3 0.93 Z011_SO3 BOC)+
F
N,f0 1-3.2.67 1-3.1.7 0, 538 0.83 X018 S01 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H
N F
N yO
1-3.2.68 1-3.1.7 a 526 1.11 V011 SO!
's H
1-3.2.69 1-3.1.7 O<o 586 1.29 VO1 1 SO1 o o F
1-3.2.70 1-3.1.7 o< 640 1.31 V01 1 SO1 (NHN
-N/
1-3.2.71 1-3.1.7 604 n.d. n.d.
- "Lo N

p>,N
1-3.2.72 1-3.1.7 Nr¨ n.d. n.d. n.d.
F
H

1-3.2.73 1-3.1.7 590 1.03 Z011 _S03 /1,1 N

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 1-3.2.74 I-3.1 0--&0 - 529 0.48 X012 SO2 F
LN
ft NH

1-3.2.75 1-3.1 543 1.04 VO1 1 SO1 I I j N,O NH2 1-3.2.76 1-3.1 543 1.02 VO1 1 SO1 F
õN J

1-3.2.77 1-3.1.4 Nyo n.d. n.d. n.d.
N OH

1-3.2.78 1-3.1 o n.d. n.d. n.d.
`=
.N

H ,,N
1-3.2.79 1-3.1.7 (j 539 1.18 V011 SO1 -'K
I NI

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 546 (M+H-1-3.2.80 1-3.1.7 a 1.106 Z020 SOI
k--ajCC¨ Boc-t-Bu) A lj ,Ny0 1-3.2.81 I-3.1.6 j,, jJ 557 1.05 V011 SO1 T-) ,N -1-3.2.82 1-3.1.6 577 0.50 X018 SO2 o I
F

LHN
LNO
1-3.2.83 1-3.1.1 >r,0 644 0.53 X012 SO!
Nj 1-3.2.84 1-3.1.7 640 0.53 X12 SO1 F

NL__N) m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method CO/li NF
1-3.2.85 1-3.1.7 551 0.59 X011 SO3 Ny0 1-3.2.86 1-3.1.7 544 0.60 X012 SO2 F,T) (7) H
NF
N I
1-3.2.87 1-3.1.7 n.d. n.d. n.d.
io o A Nõ,..p 1-3.2.88 1-3.1.2 533 1.08 VO1 1 SO1 N
0 jot t " NH, N
1-3.2.90 1-3.1.6 ,o I 563 1.29 V01 1 SO1 F
\,/

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H
F
I

1-3.2.91 1-3.1.7 n.d. n.d. n.d.
Intermediate 1-3.2.64 is separated according to method chiral SFC A to give the following intermediates as shown in Table 13.1 Table 13.1 m/z rt Intermediate Educt Structure [M+H] LC-MS method (min) 1- ' I-3.2.64.1 3.2.6 n.d. 3.828 EA.M
4 13`
N

_ I ADH 15 MEOH D
1-3.2.64.2 3.2.6 n.d. 4.631 ¨ ¨
<
EA.M

Intermediate 1-3.2.74 , 1-3.2.75, 1-3.2.81, 1-3.2.82, 1-3.2.89, 1-3.2.90,1-3.2.113, is further processed via hydrogenation before the BOC group is removed (step 4) H It ,L 0 0 1-3.2.74 1-3.2.130 To 1-3.2.74 (210 mg, 0.33mm01) in methanol (10 mL) Pd/ C (10%, 90 mg) is added. The reaction mixture is stirred at 50 C under hydrogen (50 psi) for 6 h. Then the mixture is filtered and concentrated. The crude product is carried on with step 4. Yield 85%, rn/z 531 [M+H]+, rt 0.48 min, LC-MS Method X012_S02.
In analogy the following intermediates as shown in Table 17 are prepared.
Table 17 rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 1-3.2.122 0 545 0.98 V011 SO1 3.2.75 J

H

õ
1-3.2.123 0 545 1.03 V011 SO1 3.2.75 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method r(1,1-1 `--! NH, r,o 1-3.2.124 p 3.2.81 o I 559 0.62 X011 S03 N

1-3.2.125 N 0 3.2.82 489 0.44 X018 SO2 NH

ejcid2 1-3.2.126 3.2.89 o - 516 1.02 V011 SOI
F ND

L,AH

1-3.2.127 3.2.90 475 0.41 X018 SO2 NH

CI1C'YA'NH, 1-3.2.128 :0 3.2.113 530 1.12 VOI 1 SOI

m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method INI
I- e C_) l , NH2 1-3.2.129 N . =
3.2.113 l H 530 1.00 V011 SO1 .<.?

Intermediate 1-3.2.91 is further processed in the following way:
N FIN
.7:

.......----õ,, _,..
.......--",, 1-3.2.91 1-3.2.131 N ,r0 NH
0<
To 1-3.2.91 (200mg, 0.28 mmol) in ACN (3 mL) is added p-toluene sulfonic acid monohydrate (79.67 mg, 0.42 mmol) and stirred at r.t. for 2.5h. The reaction mixture is diluted with TEA, filtered and purified by reversed phase HPLC.
Yield 68%
Intermediate 1-3.2.125, 1-3.2.126, 1-3.2.129 and 1-3.2.131 is further processed via reductive amination before the BOC group is removed (step 4) H- N2 N 0 , NH2 , F NH -3. F N
1-3.2.125 1-3.2.132 To 1-3.2.125 (130 mg, 0.266 mmol) in dichlormethane is added 3-oxotetrahydrofuran (27.49 mg, 0.319 mmol) and glacial acetic acid (15.22 aL, 0.266 mmol) and stirred for 45 min at r.t.. Sodium triacetoxyborohydride (83.1 mg, 0.372 mmol) is added and the reaction mixture is stirred at r.t.
overnight.
The reaction mixture is diluted with dichlormethane and sat. NaHCO3. The organic layer is separated, dried and concentrated. The crude product is used for the next step without further purification.
Yield 99%, m/z 559 [M+H]+, rt 0.44 min, LC-MS Method X018 S02.
In analogy the following intermediates as shown in Table 18 are prepared.
Table 18 miz rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method o N No NANH2 ,Y - 0 1-3.2.133 1-3.2.126 F NL3 586 0.50 X012_S02 , , N

miz rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method Ti)--- 0 H

NO i 1-3.2.134 1-3.2.126 0 530 1.14 V011 S01 F N
N
/

1-3.2.135 1-3.2.129 N1,,,e5,0 = ,c) 586 1.09 V011_SO1 ENF
1-3.2.136 1-3.2.131 ,L 0 o o n.d. n.d. n.d.
,.......-.., N.
The reaction time for 1-3.2.133 and 1-3.2.135 is 30 min at r.t. and for 1-3.2.134 2h at r.t. and for I-3.2.136 lh at r.t..
Intermediate 1-3.2.136 is deprotected (see example 359) and further processes via hydrogenation to give example 358:
N 1-1\11\IF ellr N ErN1.--NF
H ' H i 0 -Example 359 N- Example 358 N'.

To example 359 (20 mg, 0.047mmo1) in methanol (3 mL) Pd/ C (10%, 5 mg) is added. The reaction mixture is stirred at r.t. under hydrogen (50 psi) for 10 min. Then the mixture is filtered and concentrated. The crude product is purified by reversed phase HPLC to give example 358.
Yield 35%, m/z 425 [M+H]+, A 0.715 min, LC-MS Method Z012_SO4.
Intermediate 1-3.2.127 is further processed via alkylation before the BOC
group is removed (step 4) N I\10NH2 ei---IN =
0 ....42 -11..
F F
N N--\__ 1-3.2.127 -3.2.137 \

To 1-3.2.127 (71 mg, 0.15 mmol) in DMF (2 mL) is added 2-bromoethyl methyl ether (29.53 [IL, 0.31 mmol) and potassium carbonate (41.36, 0.266 mmol) and stirred overnight at r.t.. The reaction mixture is diluted with dichlormethane and water The organic layer is separated, dried and concentrated. The crude product is purified by reversed phase HPLC.
Yield 40%, inIz 533 [M+H]+, rt 1.05 min, LC-MS Method VO1 l_S01.
Step 3: Synthesis of Intermediate 1-3.3 To 1-3.2 (187 mg, 0.35 mmol) in DCM (12 mL) R2 (182 mg, 0.77 mmol) is added.
The reaction zo mixture is stirred for 12 h, concentrated, dissolved in ethyl acetate and extracted with 0.1M HC1 and water. The organic layer is dried over MgSO4 and concentrated. Yield 86%.
The following intermediates as shown in Table 19 are synthesized in a similar fashion from the appropriate intennediate:
Table 19 miz rt LC-MS
Intermediate Educt Structure of Intermediate [M+
(min) method H]+

1-3.3.1 1-3.2.1 533 1.21 0 <NIA
\0 0 1-3.3.3 1-3.2.5 n.d. n.d. n.d.

0 I\/-H
Nµ
A 0 ) 1-3.3.4 1-3.2.8 0 n.d. n.d. n.d.

0 o 1-3.3.5 1-3.2.15 626 n.d. n.d.

miz rt LC-MS
Intermediate Educt Structure of Intermediate [M+
(min) method H]+
o 1-3.3.6 1-3.2.16 4 0 n.d. n.d. n.d.

1-3.3.7 1-3.2.17 0 o 0 n.d. n.d. n.d.

H
N

0 ' 1-3.3.8 513 0.55 3.2.130 2 -N
Ny0 1-3.3.9 1-3.2.75 525 1.17 N

1-3.3.10 VO 1 l_SO
1-3.2.76 525 1.15 miz rt LC-MS
Intermediate Educt Structure of Intermediate [M+
(min) method H]+
o 1,114L'Llo'''.!. NF

1-3.3.11 0,< 527 1.15 3.2.122 =`"s''0 1 Ns.,) (:) H
;1 1- N _..C) I V011 SO
1-3.3.12 1 527 1.12 3.2.123 c)< , , 1 0 ---.'-'0 o ' '-i; ' 1-3.3.13 1-3.2.78 ---, F -r-- -1 496 0.54 ..N.
,L(1,11111,_,N
1-3.3.14 I-cr'N'Ll 0 541 0.71 X011-503 3.2.124 "- F - - - ' - ' - 'IN
-co ,,, ,N
1-3.3.15 I- X018 SO
-,--z 541 0.49 3.2.132 ,_ 0 F--- c) 2 F '' N
J
,F--miz rt LC-MS
Intermediate Educt Structure of Intermediate [M+
(min) method H]+

NO

you SO
1-3.3.16 ll 568 1.22 3.2.133 1 H

1-3.3.17 0 512 1.26 3.2.134 1-3.3.18 515 1.17 VO1 1 SO
3.2.137 1 [CH
fr\l),:rLO V011 SO
1-3.3.19 512 1.25 3.2.128 )LHN N 0 V011 SO
1-3.3.20 568 1.23 3.2.135 o= 1 Step 4: Synthesis of Example 3 To 1-3.3 (155 mg, 0.30 mmol) in acetonitrile, sodium iodide (134 mg, 0.89 mmol) and chlorotrimethylsilane (114 gl, 0.89 mmol) are added. The mixture is stirred for 2 h, then methanol is added, stirred for additional 30 min and then concentrated. The residue is purified by reversed phase HPLC. Yield 62%, m/z 420 [M+H]+, A 0.41 min, LC-MS Method X016_S01.
Method A2.2 Synthesis of (1S,2S,4R)-N-K1S)-1-cyano-2-[2-fluoro-4-(4-phenylpiperazin-1-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 32) NNTrrNINI-1 N
e.õ.,0: .
, .,.., 0 R112 F
,,,,52 40 , 'I
F B L,N
I
(:)----1-3.1.2 1-3.2.4 cti.)-H N
NH F
___________________________ 7.
0 N'...1 N
Example 32 Step 1: Synthesis of intermediate 1-3.2.4 To 1-3.1.2 (150 mg, 0.30 mmol) in DCM (6 mL), triethylamine (85 jiL, 0.61 mmol), R112 (55.22 15 mg, 0.34 mmol) and copper(TT)acetate (85 mg, 0.47 mmol) are added. The mixture is stirred for 72 h at r.t.. 7M ammonium solution in methanol is added, the mixture is concentrated. The residue dissolved in acetonitrile and filtrated. The product is purified by reversed phase HPLC. Yield 54%, nilz 548 [M+H]+, rt 1.37 min, LC-MS Method V011_S01.

The following intermediates as shown in Table 14 are synthesized in a similar fashion from the appropriate intermediate Table 14 m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method H N
I-3.2.7 1-3.1.2 528 1.10 V011 SO1 H
1-3.2.9 1-3.1.2 0.1 1411 550 1.11 V011 SO1 LNP
N-Th H
1-3.2.14 1-3.1.2 - 556 1.20 V011 SO1 H N
1-3.2.19 1-3.1.2 -544 1.22 VO1 1 SO1 Nr H õN

1-3.2.20 1-3.1.2 - (M+H- 1.20 V011_SO1 i201411 = N BOC)+

m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method H õN
eN-r-F
1-3.2.22 1-3.1.2 o 0 110 530 1.13 V011 SO1 1\1') NyO E
1-3.2.24 1-3.1.2 4111 512 1.28 V011 SO1 V

H
TeL,Noy- F
1-3.2.25 1-3.1.2 500 1.21 VO 1 1 S01 1-3.2.26 0 H N
(forms F
1-3.1.2 516 1.02 V011 SO1 together with 0 I-3.2.27) 1-3.2.27 (forms F
1-3.1.2 516 1.02 VO 1 1 SO1 together with N-Th I-3.2.26) H
eLõNo-r. F
1-3.2.28 1-3.1.2 '-e-2 558 1.25 VO 1 1 501 m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method H
1-3.2.29 NO
1-3.1.2 500 1.21 V011_501 H N
[te,f,L0 E
1-3.2.30 1-3.1.2 ,,es2 140 556 1.13 V011 501 Lõ0 Lir\FI
1-3.2.31 1-3.1.2 NO

499 1.49 VO1 1 501 H
1-3.2.32 1-3.1.2 N11 514 1.21 V011 SO1 H
1-3.2.33 1-3.1.2 NO
I410 471 1.39 V011_501 m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method eH õN
NO-r-F
I-3.2.34 1-3.1.2 I -..,z...$) 140 N 472 1.36 VO11_SO1 N

eH õN
N0,-,,_ -F
I-3.2.35 1-3.1.2 I -..4.2 0 N 473 1.17 V011_S011 , I-3.2.92 I-3.1.2 NY z < n.d. 0.67 X011_SO3 0, el N -'-\
c_2--yj, N, F
H -õN
I-3.2.93 N,0 , I-3.1.2 iti..õ,., 1- 540 1.09 VO 1 1 SOI
1----õ, ,- --,N----,_,----,i _ z .C`-r\I -N
T - -1-3.2.94 1-3.1.2 0,,. I 561 1.07 VO 1 1 SO1 i-- ---N----- F
0 " -----S' m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method r....011LH
N, F
1-3.2.95 1-3.1.2 559 1.08 V011 SO1 o,<

1-3.2.96 1-3.1.2 528 0.78 X011_SO3 H
N F
A)\lz,0 1-3.2.97 1-3.1.2 r - 528 0.77 X011 SO3 N-1-3.2.98 1-3.1.7 542 1.26 V01 1 SO1 1-3.2.99 1-3.1.7 12\10 512 1.26 V011 SO1 "\) '?1" F
1-3.2.100 o 1-3.1.7 --f-526 0.72 X011 S03 `, /

m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method H
N F
1-3.2.101 1-3.1.7 500 1.24 VO1 1 SO1 N-LHN
1-3.2.102 I-3.1.4 r"
= Nj 486 1.13 V011 SO1 FS
H

o 1-3.2.103 1-3.1.2 W-1 584 1.36 VO1 1 SO1 H
F
1-3.2.104 1-3.1.7 512 1.31 VO1 1 SO1 0,..<

m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method H
NyO
1-3.2.105 1-3.1.7 0,.< 410 568 0.75 X011 SO3 H
TN)Lo F
1-3.2.106 1-3.1.7 498 1.20 V01 1 SO1 H
Teri%
1-3.2.107 1-3.1.7 542 1.13 VO1 I SOI
N

m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method H N
es, 0 F
-V =
1-3.2.108 1-3.1.7 512 1.29 V011_SO1 0.<
N

H
vto,, 1-3.2.109 1-3.1.2 0...<
572 1.36 V01 1 S01 NO
C)<

H
F
1-3.2.110 1-3.1.2 1\11 556 0.65 X011_S03 m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method H
1-3.2.111 1-3.1.1 528 0.79 X011 S03 H ,N
' F
1-3.2.112 fõ7.0 _ 1 1-3.1.7 513 0.69 X011 S03 ,b F
1-3.2.114 1-3.1.7 n.d. n.d. n.d.
H

m/z LC-MS
Intermediate Educt Structure of Intermediates rt (min) [M+H]+ method eH N

1-3.2.115 1-3.1.7 si:2 542 0.99 Z011 S03 , H
1-1,..' N.) - F
1-3.2.116 1-3.1.7 [
1.1 H
NO) 542 1.017 Z011 SO3 A NI' For the synthesis of the intermediates 1-3.2.117 and 1-3.2.118 to the cduct 1-3.1.2 with the appropriate amine in Me0H 0.14 eq copper(I)oxide is added (as shown in Table 15).
Table 15 m/z 1ntermedi rt Educt Structure of Intermediate [M+H LC-MS method ate (min) 1+

e N.õ,r0 i 422(M
j_ ol< 40 ,N
1-3.2.117 11.2 +H- 1.32 VO1 1 SO1 F F BOC)+
F

m/z 1ntermedi rt Educt Structure of Intermediate [M+H LC-MS method ate (min) 1+
ii,N
N.
. N t,0 O.
1-3.2.118 526 1.28 VO 1 1 SO1 3.1.2 o' H
N

1-3.2.119 3.2.1 o 498 1.84 I OJH 10 MEOH DEA.M

?,H
t N F
NO
1-3.2.120 3.2.1 O< 525 1.10. V011 SO1 0 \
The synthesis of1-3.2.119 proceeds in the following way: 1-3.2.118 (785 mg, 1.49 mmol) is dissolved in THF. LiOH (1.5 eq.) as aq. solution is added and stirred at r.t.
for 9 h.The product mixture is acidified with 1 M HCI to pH 5 and purified by HPLC-MS. Yield: 61 %.
The amide coupling for synthesis of intermediate 1-3.2.120 proceeds in the following way:
1-3.2.119 (40 mg, 0.08 mmol) HATU (33.6 mg, 0.088 mmol) and DIPEA (55.3 L, 0.322 mmol) are dissolved in DMF. The mixture is stirred at r.t. for 15 min. Dimethylamine (120.6 L, 0.241 mmol) is added, and the reaction mixture is stirred at r.t. for 1.5 h. The product mixture is separated by HPLC-MS .
The fractions are combined and freeze-dried. Yield: 85%.

The following intermediate as shown in Table 16 is synthesized in a similar fashion from the appropriate intermediate Table 16 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H
F
,0 I
1-3.2.121 ,N
N 567 1.10 V011 SO1 3.2.119 The reaction conditions for 1-3.2.94 and 1-3.2.95 differ: Pyridine instead of TEA is used.
The reaction conditions are 80 C overnight.
The reaction conditions for 1-3.2.111 differ: 2eq of N-Methylmorpholine N-Oxid is added to the reaction.
Step 2: Synthesis of example 32 To 1-3.2.4 (82 mg, 0.15 mmol) in acetonitrile, p-toluenesulfonic acid monohydrate (95 mg, 0.50 mmol) is added and stirred overnight at r.t.. The reaction mixture is basified with ammonium solution. 0.5 mL water and 1 mL ACN are added. The precipitate is filtered off, washed with ACN
and dried. The crude product is triturated with aq. sodium hydrogencarbonate solution, filtered by sunction and dried. Yield 31%, m/z 448 [M+H]+, rt 1.28 min, LC-MS Method VOl1_S01.
Method A3 Synthesis of (1S,2S,4R)-N-[(1S)-1-eyano-2-[2-fluoro-4-(3-methylsulfonylphenyl)phenyllethy1]-3-azabicyclo[2.2.1]heptane-2-earboxamide (Example 4) OH
NyO
H N

14111 Br __________ 0 0 Br Br 1-2.2 1-4.1 1-1.1 HON

H ,.1\1 - F
=

F
NH

/ S' 0 Example 4 1-4.3 Step 1: Synthesis of Intermediate 1-4.1 To 1-1.1 (5.00 g, 14 mmol) in acetonitrile (250 mL) p-toluenesulfonic acid monohydrate (3.05 g, 16 mmol) is added and the mixture is stirred for 3 d. The precipitate is filtered off and the solution is washed with acetonitrile. The residue is stirred with aq. NaHCO3 solution (2%), and extracted with ethyl acetate. The organic layer is dried over MgSO4 and concentrated. Yield 78%, m/z 243/245 [M+H]+, rt 0.76 min, LC-MS Method V018_SO1.
io The further intermediates belong to the following description Synthesis of 2-amino-3-(4-bromo-2-fluoro-phenyl)propanenitrile Br Br Br N
F

N N
Br R19 1-4.0 1-4.1.1 Step 1.1: Synthesis of Intermediate 1-4.0 (compare with synthesis of Intermediate I-7.1) To R19 (28.1 g, 104 mmol) and R20 (21.0 g, 95 mmol) in DCM (130 mL) benzyltrimethyl-ammonium chloride (1.77 g, 9.5 mmol) is added. Under strong stirring water (8 mL) and aq. NaOH
solution (19mol/L, 9 mL) are added (exothermic reaction). The reaction mixture is stirred for 12 h.
Water is added and the product is extracted with DCM. The organic layer is dried over MgSO4 and concentrated. The crude product is used in step 2. Yield >95%, rt 1.56 min, LC-MS Method V003_003.
The following intermediates as shown in Table 20 are synthesized in a similar fashion from the appropriate intermediate ((R, 5) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 20 m/z LC-MS
Intermediate Structure rt (min) [M+H]+ method Br 1-4Ø1 n.d. n.d. n.d.
Br FF
-1\1 1-4Ø2 425/427 1.51 VO1l_SO1 N

m/z LC-MS
Intermediate Structure rt (min) [M+H]+ method Br CI
LN
1-4Ø3 n.d. n.d. n.d.
N
Br 1-4Ø4 0 .1\1 495/497 0.96 X018_SO1 NQ
Step 1.2: Synthesis of Intermediate 1-4.1.1 (compare with synthesis of Intermediate 1-7.2) To 1-4.0 (40.8 g, 100 mmol) in dioxane (400 mL) hydrogen chloride solution in dioxane (4 mon, 27.5 mL, 9.5 mmol) is added. The reaction mixture is stirred for 12 h. Aq.
hydrochloric acid (1 mon, 100 mL) is added and the mixture is stirred for additional 2 h. The reaction is concentrated, the residue is stirred with acetonitrile and the precipitate is filtered off.
Yield 49%, m/z 243 [M+H]+, rt 0.42 min, LC-MS Method X001_004.
The following intermediates as shown in Table 21 are synthesized in a similar fashion from the appropriate intermediate ((R, 5) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 21 m/z rt LC-MS
Intermediate educt Structure [M+H]+ (min) method m/z rt LC-MS
Intermediate educt Structure [M+H]+ (min) method Br 1-4Ø1 F 261 0.35 Z001_002 Br 1-4.1.1.2 1-4Ø2 FAF 261/263 0.34 V012_SO1 N

Br 1-4.1.1.3 1-4Ø3 01 259 0.39 X001_004 N

Br 1-4.1.1.4 1-4Ø4 010 ON 331/333 0.48 V018_SO1 Step 2: Synthesis of Intermediate 1-2.2 To R5 (2.82 g, 11 mmol) in dry DCM (150 mL) diisopropylethylamine (5.8 mL, 33 mmol) and HATU (5.1 g, 13 mmol) are added and the mixture is stirred for 30 min. Then a solution of 1-4.1 (2.75 g, 11 mmol) in DCM (50 mL) is added and stirred for 12 h. The mixture is washed with water, aq. K2CO3 solution (5%) and 1 M HC1. The organic layer is dried over MgSO4 and concentrated. Yield 68%, m/z 466/468 [M+H]+, rt 1.25 min, LC-MS Method VO1 l_SOL
The following intermediates as shown in Table 22 are synthesized in a similar fashion from the appropriate intermediate: ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group) Table 22 Intermediate cduct Structure m/z [M+H]+ rt (min) LC-MS method 1-4.2.1 1-4.1.1 --. 0 466 0.78 X001 004 )\ F
Br N
0 I I F Br AN:
1-4.2.2 1-4.1.1.1 H484 1.29 V011 SO1 \r 0 )<õ0 N --F
1-4.2.3 1-4.1.1.2 ,,,L 0 484/486 1.29 V011 S01 ')\ F
Br N
0 I I Br N
1-4.2.4 1-4.1.1.3 n.d. n.d. n.d.
eH
CI
\r0 ).0 r\41,(F1 N

1-4.2.5 1-4.1.1.4 .)\ 554 1.42 VO1l_SO1 Br i Step 3: Synthesis of Intermediate 1-4.3 To 1-2.2 (300 mg, 0.64 mmol) in acetonitrile (7.5 nit) R9 (142 mg, 0.71 mmol) is added. The mixture is purged with argon 1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (42 mg, 0.10 mmol) and aq. sodium carbonate solution (2 mol/L, 0.64 mL) are added and heated to 70 C for 2,5 h. Ethyl acetate and water are added to the reaction mixture. The organic layer is washed with aq. NaHCO3 solution (5%) and water. The organic layer is dried over MgSO4 and concentrated. Yield raw product >95% nilz 442 [M+H]+, rt 0.93 mm, LC-MS Method Z018_SO4.
The following intermediates as shown in Table 23 are synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile 1() group):
Table 23 rt LC-MS
Intermediate Educt Structure of Intermediate m/z [M+1-1]+
(min) method H N
F
I-4.3.1 I-4.2.1 NO / 567 1.19 V011 SO1 O..
=
S' 0 r\ti,FI õAV
N
I-4.2.1 0 533 1-4.3.2 0 0 0.75 X001_004 H (Cf .1\1 NrITO
1-4.3.3 1-2.2 I 442 0.92 Z018 SO4 rt LC-MS
Intermediate Educt Structure of Intermediate m/z [M+I-1]+
(min) method H N
r\===Iri,N

1-4.3.4 0 585 1.20 VO1 1 SO1 N
1\11,,,rH
N

1-4.3.5 1-4.2.1 0 0 519 0.62 Z001_002 H N
111\l'ej,IfLO
1-4.3.6 1-2.2 429 0.95 Z018 SO4 sç
1-4.3.8 1-4.2.2 /\-\ F 551 1.22 VO1 l_SO1 %-N

1-4.3.9 1-4.2.1 ip n.d. 1.39 V003_003 Intermediate Educt Structure of Intermediate m/z [M+H]+
(min) method H N
eN
r0 1-4.3.10 1-4.2.1 543 0.57 001 CA07 F
H2N ¨

H

1\1);0 1-4.3.11 1-4.2.1 518 0.55 001 CA07 F

N
1-4.3.12 1-4.2.1 0 0 0 n.d. n.d. n.d.

eH
N
lyL
1-4.3.13 1-4.2.1 o 532 0.57 001 CA07 F
NH

H
TIN
N'llyL 0 1-4.3.14 1-4.2.1 556 0.60 001 CA07 F
H

Intermediate Educt Structure of Intermediate m/z [M+H]+
(min) method H N
N
1-4.3.15 1-4.2.3 0 0 0 551 1.21 VOl1_SO1 NN

eH
N
yL 0 1-4.3.16 1-4.2.1 F 506 0.56 001 CA07 eH
N
ly0 1-4.3.17 1-4.2.1 541 0.60 001 CA07 F
S--C) /II

eN
rH0 1-4.3.18 1-4.2.1 542 0.56 001 CA07 F
Q.0 H N

N
N

1-4.3.19 1-4.2.5 621 1.33 V011_SO1 rt LC-MS
Intermediate Educt Structure of Intermediate m/z [M+1-1]+
(min) method H
N
TIN)y.L.0 1-4.3.20 1-4.2.1 F 556 0.60 001 CA07 jj -S-H
CfN
1Nr:IrL 0 1-4.3.21 1-4.2.1 556 0.62 001 CA07 F
II

N
Vly,L 0 1-4.3.22 1-4.2.1 F 532 0.58 001 CA07 H
N
1-4.3.23 1-4.2.1 n.d. 1.22 Z018 SO4 NH

rt LC-MS
Intermediate Educt Structure of Intermediate m/z [M+H]+
(min) method r\j,4trH N
N
1-4.3.24 1-4.2.4 0 0 0 n.d. n.d. n.d.
-)\ a H N
N
Vy'L
1-4.3.25 1-4.2.1 506 0.55 001_CA07 F

H N
N
1-4.3.26 CCIN'.j:L' 0 1-4.2.1 0. / n.d. n.d. n.d.

H N
TIN
N)y,L
1-4.3.27 1-4.2.1 F 534 0.63 001 CA07 H N
Cet0 F
D
1-4.3.28 1-2.2o 500 0.98 VO1 1 SO1 1) rt LC-MS
Intermediate Educt Structure of Intermediate m/z [M+H]+
(min) method H õN
1-4.3.29 1-2.2 442 (M+H-1.09 Z018 SO4 0 BOC)+
\
S

H N
j?,rLO F 414 (M+H-1-4.3.30 0.60 ZO1l_S03 4.3.29 0 BOC)+
\
s OH

H õN
F
I - 408 (M+H-1-4.3.31 1-2.2 0 I 0.93 Z018 SO4 BOC)+

OH
The reaction conditions for I-4.3.28 differ: Under argon atmosphere 1-2.2 (250 mg, 0.54 mmol), potassium carbonate (150 mg, 1.07 mmol), copper (I) iodide (10 mg, 0.05 mmol), N,N'-dimethylethylendiamine (25 i.tL, 0.23 mmol) and 4-methyl-piperazin-2-one (75 mg, 0.66 mmol) in dioxane (10 mL) are heated to 80 C for 8 d. The reaction mixture is filtered and the solution is concentrated. The residue is purified by reversed phase HPLC. Yield 30%, m/z 500 [M+H]+, rt 0.98 min, LC-MS Method V01 l_S01.
The synthesis of 1-4.3.30 proceeds in the following way: 1-4.3.29 (509 mg, 0.94 mmol) is dissolved io in dioxane. LiOH (1.5 eq.) as aq. solution is added dropwise to the solution and stirred at r.t. for 8 h.The product mixture is extracted 2x with DCM. The organic layer is extracted twice with water.
The water phase is acidified with 1 M HC1 to pH 4, the solvent removed in vacuo to yield the crude product, which is purified by HPLC-MS (Gilson, mass flow 120 mi./min, 10 uM, 200 g Xbridge RP18, ACN/water/NH3). Yield: 44 %.

Intermediate 1-4.3.19 is additionally treated with BBr3 to give example 120:

N N

1-4.3.19 example 120 1-4.3.19 (600 mg, 0.97 mmol) in DCM (50 mL) is stirred at -5 C. Then boron tribromide solution (1 mol/L in DCM, 2.90 mL) is added dropwise. The reaction mixture is stirred at 0 C for 90 min and then stirred at room temperature for additional 12 h. The mixture is cooled down again to -5 C
and is quenched with conc, ammonia solution. The mixture is concentrated and purified by to reversed phase HPLC. Yield 5%, m/z 429 [M+H]+, rt 0.81 min, LC-MS Method V018_SO4.
Additional step: Amide coupling to afford 1-4.3.32 The amide coupling for synthesis of intermediate I-4.3.32 proceeds in the following way: 1-4.3.30 (35 mg, 0.068 mmol) TBTU (45 mg, 0.14 mmol) and N-methylmorpholine (75 [tL, 0.68 mmol) are dissolved in DMF. The mixture is stirred at r.t. for 5 min. 0.5 M ammonia in dioxane (2 mL, 1 mmol) is added, and the reaction mixture is stirred at r.t. for 12 h. The product mixture is separated by HPLC-MS (Waters, 30x100 mm, 10 [0\4, sunfire RP18, ACN/water/TFA). The fractions are combined and freeze-dried. Yield:59%.
zo The following amide intermediates as shown in Table 24.1 are synthesized in a similar fashion from the appropriate intermediates:
Table 24.1 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 0 ________________________________________________________________ LIRINF

N

1-4.3.32 (M+H- 0.89 Z018_SO4 4.3.30 \ BOC)+
s NH, cj427 1-4.3.33NO (M+H- 0.92 Z018_SO4 4.3.30 \ BOC)+
s NH

,f 1-4.3.34 N o (M+H- 1.00 Z018_SO4 4.3.30 0 \ BOC)+
S N

31) :Vr\FI 467 I
1-4.3.35 (M+H- 0.99 Z018_SO4 4.3.30 ------\ BOC)+
S r1) k r - ''1\1 1-4.3.36 (M+H- 0.95 Z018_SO4 4.3.30 0 \ BOC)+
S N

lytH

(M+H- 0.95 Z018_SO4 4.3.31 1-4.3.37 0 BOC)+
NH

H N _________________________________ N,r0 z 1-4.3.38 (M+H- 0.75 Z018_SO4 T-4.3.31 0 BOC)+
CN) H

eN0-<_ - F
T-4.3.31 1-4.3.39 (M+H- 0.91 Z018_SO4 0 BOC)+
HN

NO
F

1-4.3.40 (M+H- 0.94 Z018_SO4 4.3.31 0 BOC)+
HN
H N
N
yL

1-4.3.41 (M+H- 0.93 Z018_SO4 4.3.31 0 BOC)+

H

I-4.3.42 (M+H- 1.02 Z018 SO4 4.3.31 I 0 BOC)+
N

H N

(M+H- 0.94 Z018_SO4 4.3.31 I-4.3.43 0 BOC)+
, N
H

1-4.3.44 (M+H- 0.97 Z018_SO4 4.3.31 0 BOC)+
SiN

I-1-4.3.45 IO (M+H- 0.89 Z011_803 4.3.30 \
S N BOC)+

-1-4.3.46 1-o I (M+H- 0.90 Z018_804 4.3.30 KN--) BOO+

o 1,,,..*1.1;ii I-1-4.3.47 NT ...,õ1,, ,)----- (M+H- 0.97 Z011_503 4.3.30 /N- BOC)+
's "\\0 o 1,,T,Airl, *NF

I- 1,N0 .,,,,cj, 1 1-4.3.48 (M+H- 0.91 Z011_503 4.3.30 ii-,N) s')( BOC)+

o I- N -0': I
1-4.3.49 - 1 T' - , N /j" "-- (M+H- 0.98 Z011_503 4.3.30 \
_N--,) BOC)+
o 'INI'l II' 0--.0 " ' 483 I-1-4.3.50 ; (M+H- 0.90 Z011_503 4.3.30 -A F ` ,9 i , -- s BOC)+
----- 71--, \-2 o Ili F ,z I- 424(M+H-1-4.3.51 N,..r, .,,,,,..... i ,L0 0.86 Z011 503 _ 4.3.30 -,....,<_o , ,--- 'N
1 N.-) BOC)+
/ \
s o o itT)1,,o, 1.,,,,ry I- A 0 - ,L, ,F 564(M+H-1-4.3.52 - d /-------t-r 0.98 Z018 504 _ "
4.3.30 ,,,0 L,õ,, /-1,1 F
BOC)+ (\
o o l :L N 510 I-1-4.3.53 (M+H- 0.85 Z011_503 ..-:).].
4.3.30 "<- ni /,0 \\ ¨ BOC)+
's-o 1-4.3.54 I- [,,,,N.,to ), L 1 /------, (M+H- 0.89 Z011_503 ,----N 6 4.3.30 \---.<_ ---- ), Ni___ Cs) BOC)+
--'1 H õ--N
I-0"-- 0 0 497 1-4.3.55 4.3.30 (M+H- 0.91 Z011_503 I \;
"S NH
/ ( BOC)+
/ >
'o /
o ( \i)J-11,N

I- N ,0 = , 1-4.3.56 "
I (M+H- 0.84 Z011_503 2.3.41 -.....,<.0 =.--,õ..--. T., s- BOC)+
õ- -NH2 lfi ,ry T ----- F
I- 0 ..r., 519(M+H-1-4.3.57 .6 --__ 1,--- 0.94 Z018 _SO4 2.3.41 BOC)+
/
s-.!?
-----N -----\'N

,,INI, õ0õ NF
I- i N,r0 ,c1i, 522(M+H-1-4.3.58 0.87 Z018 _SO4 2.3.80 12 BOC)+

H ,,,..,N
N. F
LI\Iõ ,0 .;, j, I- 'r j 397(M+H-1-4.3.59 o 0.86 Z018 504 2.3.81 --<___ ' '-'--.._.¨o I \ BOC)+ ¨
\/
\
H2N-----o o Li-11, 1- NOf0 -,., 503(M+H-1-4.3.60 .õ,._e_o -.1...,,,,,,ir 0.88 Z011 _S03 2.3.81 I BOC)+
./\'---N'---e--[1T' N
N y0 .Ny- ,,,,,,,,,FL,,,, I- 480(M+H-1-4.3.61 --le? L-----11To 0.74 2018 504 _ 2.3.81 BOC)+
---o ( ) o , ?,H N
I N, F
N,f0 õ,.: j I- 425(M+H-1-4.3.62 _o ,(:) 0.91 2018 _SO4 2.3.81 ' BOC)+
-Lo H

?LH , , :õN
V N F

I- Al\lõ.T.,,,,,0 .-,I, ,, 1-4.3.63 ___:_o .J... - (M+H- 1.02 2018_504 2.3.82 ..,-- ----,-,..
I
-...,% BOC)+
0--..-----'NH2 õ4õ.õ.......Võir-li, ,N
N0 .- F,1 490 1-4.3.64 2.3.82 I __ (M+H- 0.76 2018_504 J, 0 N BOC)+
r-'1 (_,N1.

ry 1- 't N y,0 467 1-4.3.65 I (M+H- 0.91 Z018_504 2.3.80 O BOC)+
N o 0 \

N
N, 480(M+H-1-4.3.66 0 i1 0.73 Z018 504 2.3.80 BOC)+
0' The reaction conditions for I-4.3.63differ: 1-2.3.82 (100 mg, 0.197 mmol), HATU (82.4 mg, 0.217 mmol) and DIPEA (68 L,2eq) are dissolved in DMF. The mixture is stirred at r.t. for 30 min.
Ammonium chloride (63.2mg, 1.182 mmol) and DIPEA (204 pL,6eq) are added, and the reaction mixture is stirred at r.t. for 3 h. The product mixture is separated by HPLC-MS (Waters, 30x100 mm, 10 laM, xBridge RP18, ACN/water/TFA). The fractions are combined and freeze-dried.
Yicld:27/0.
The reaction conditions for 1-4.3.65 and 1-4.3.66 differ: DCM is used as solvent instead of DMF.
Step 4: Synthesis of Example 4 1-4.3 (348 mg, 0.64 mmol) in formic acid is stirred for 10 min at 40 C. The reaction solution is diluted with DMF and directly purified by reversed phase HPLC. Yield 86%, m/z 442 [M+H]+, rt 0.65 min, LC-MS Method Z018_SO4.
Method A4 Synthesis of (1S,25,4R)-N-1(1S)-1-cyano-2-[2-fluoro-444-(111-indo1-5-yl)triazol-1-yl]phenyllethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 5) r o _____________________________________________________________ 1 0_o 0 Nõ
Br N.
1-5.1 1-2.1 H
HN
R10 N\
N, N. +
N õ
1-5.2 0 ).."'"
Example 5 Step 1: Synthesis of Intermediate 1-5.1 1-2.1 (2.26 g, 4.7 mmol), sodium azide (0.61 g, 9.3 mmol), trans-(1R,2R)-N,N'-bismethy1-1,2-cylcohexane diamine (147 .1, 0.93 mmol), copper(T)iodide (89 mg, 0.47 mmol) and L-ascorbic acid sodium salt (92 mg, 0.47 mmol) are dissolved in ethanol/water = 7/3 (60 mL). The mixture is heated to 100 C for 1.5 h. Water and DCM are added to the reaction mixture.
The organic layer is washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by reversed phase HPLC. Yield 85% m/z 447 [M+H]+, rt 0.91 min, LC-MS Method Z018_SO4.
Step 2: Synthesis of Intermediate 1-5.2 To 1-5.1 (1.76 g, 3.9 mmol) in anhydrous DCM (30 mL) R2 (2.35 g, 9.9 mmol) is added. The reaction mixture is stirred for 11 h. The reaction mixture is extracted with 0.5M HO and water.
The organic layer is extracted with half saturated Na2CO3 solution, water and brine. The residue is purified by reversed phase HPLC. Yield 54% rn/z 329 [M+H]+, rt 0.96 min, LC-MS
Method Z018_SO4.
Step 3: Synthesis of Example 5 To R10 (28 mg, 0.20 mmol) in DMSO (1.3 mL) 1-5.2 (43 mg, 0.10 mmol) is added.
Then copper(II) sulfate pentahydrate (2.2mg, 0.01mmol), L-ascorbic acid sodium salt (11 mg, 0.05 mmol) and 100pI water are added. The reaction mixture is stirred for 12 h. The reaction mixture is diluted with DMF and directly purified by reversed phase HPLC. The achieved substance is dissolved in formic acid, stirred at 40 C for 10 min and the reaction mixture is purified again by reversed phase HPLC. Yield 34% in/z 470 [M+H]+, rt 0.70 min, LC-MS Method Z018_SO4.
Method A5 Synthesis of (1S,25,4R)-N-[(1S)-1-eyano-2-[2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 6) H
H
e E
N.. CN
)-t, D litr&NLNH, , NH2 H Rli ________________________________ m.

B...; F N
F
1 1\1 1-3.1 1-6.1 o 0 0 o4 .õ r / N¨S¨N.¨\ 8 LH N ¨ _. N

' e, H , F
0 :
-`e",- = NH E
3.
= - .. , e_ . 52 F N-. 1-6.2 N--[N,,N. Example 6 Step 1: Synthesis of Intermediate 1-6.1 To 1-3.1 (90 mg, 0.20 mmol) in DCM (4 mL), triethylantine (60 iaL, 0.43 mmol), R11 (23 L, 0.21 mmol) and copper(II)acetate (55 mg, 0.30mmo1) are added. The mixture is stirred for 12 h. 7M
ammonium solution in methanol is added, the mixture is concentrated. The residue dissolved in acetonitrile and filtrated. The product is purified by reversed phase HPLC.
Yield 32%, in/z 504 [M+H]+, rt 1.00 min, LC-MS Method VO1 1 S01.

The following intermediates as shown in Table 24.2 are synthesized in a similar fashion from the appropriate intermediates:
Table 24.2 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method H C)11 ,VN 0 NH2 1-3.2.89 F N 606 1.40 V011 3.1.5 rtj o 1-3.2.113 606 1.37 V011 3.1.5 1\
F
Step 2: Synthesis of Intermediate 1-6.2 To 1-6.1 (40 mg, 0.08 mmol) in DCM (1 mL) R2 (35 mg, 0.15 mmol) is added. The reaction mixture is stirred for 12 h. The reaction mixture is concentrated and the residue is purified by reversed phase HPLC. Yield 67%, m/z 486 [M+H]+, rt 1.12 min, LC-MS Method V011 S01.
Step 3: Synthesis of Example 6 To 1-6.2 (25 mg, 0.05 mmol) in acetonitrile, p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) is added and stirred for 12 h. The product is purified by reversed phase HPLC. Yield 86%, m/z 386 [M+H]+,rt 0.98 min, LC-MS Method VOII_SOL
Method B
Synthesis of (1S,2S,4R)-N-12-14-(1-acetyl-5-methyl-pyrazol-3-y1)-2-fluoro-phenyl]-1-cyano-ethyl1-3-azabicyc1012.2.11heptane-2-carboxamide (Example 7) \o N

N
N
O Br F
__________________________________ 3.
Nr \
N-N
\
R12 1-7.2 N-N
1-7.1 OH cõ.,,H cra,):LH
N
o NO
NO
R5 C) -11==
\
N-N N-N
Example 7 1-7.3 Step 1: Synthesis of Intermediate I-7.1 R12 (340 mg, 1.54 mmol), R13 (480 mg, 1.54 mmol), benzyltrimethylammonium chloride (29 mg, 0.15 mmol) and DCM (10 mL) are put together. Under stirring water (250 !IL) and sodium hydroxide solution (19 mon, 146 uL) are added. The reaction mixture is stiffed for 1 h.
Half saturated brine and DCM are added. The organic layer is concentrated and purified by reversed phase HPLC. Yield 22%. m/z 451 [M+H]+, rt 1.48 min, LC-MS Method VO1 l_S01.
The following intermediate as shown in Table 25 are synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 25 miz rt LC-MS
Intermediate Structure [M+H]+ (min) method miz 11 LC-MS
Intermediate Structure [M+H]+ (min) method 0 Br 1-7.1.1 N
447/449 0.78 X012_SO1 N

, 0' 1-7.1.2 356 0.75 X012_SO1 N
1-7.1.3 500 0,95 X012_SO1 N
N
N
1-7.1.4 413 0.90 X012_SO1 miz 11 LC-MS
Intermediate Structure [M+H]+ (min) method N
JcI
1-7.1.5 0 N 401 0.86 X012_SO1 N
N
1-7.1.6 500 0.95 X012_SO1 0 B r N
1-7.1.7 466 0.82 X011_SO2 N
Step 2: Synthesis of Intermediate 1-7.2 To I-7.1 (155 mg, 0.34 mmol) in dioxane (6 mL) aq. HC1 (1 mol/L, 361 L) is added. The reaction mixture is stirred for 1 b. 135 iaL aq. HCI (1 M) is added and stirred for additional 30 min. The product is purified by reversed phase HPLC. Yield >95%. m/z 287 [M+H]+, rt 1.01 min, LC-MS
Method VO1 l_S01.
The following intermediates as shown in Table 26 are synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile to group):
Table 26 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+F-1]+ (min) method 0 Br I-7.1.1 1-7.2.1 284/286 0.48 X012_SO1 N

I
.N
0' I-7.2.2 I-7.1.2 n.d. n.d. n.d.
N

1-7.2.3 1-7.1.3 0 N 336 0.56 X012 S01 N
1-7.2.4 I-7.1.4 NH2 249 0.47 X012 SO1 N
1-7.2.5 1-7.1.5 227 0.43 X012_SO1 NH

N
1-7.2.6 I-7.1.6 NH2 336 0.55 X012_SO1 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method 0 Br 1-7.2.7 1-7.1.7 318/320 0.48 X011 SO2 N (M+H20) Step 3: Synthesis of Intermediate 1-7.3 To R5 (50 mg, 0.21 mmol) in DMF (1.5 mL) HATU (87 mg, 0.23 mmol) and diisopropylethylamine (143 [LI-, 0.83 mmol) are added and the reaction mixture is stirred for 15 min. Then intermediate 1-7.2 (87 mg, 0.22 mmol) is added and the mixture stirred for 12 h. The reaction solution is purified by reversed phase HPLC. Yield 81%, nilz 510/454/410 [M+H]+, rt 1.28 min, LC-MS Method VO1 l_S01.
The following intermediates as shown in Table 27 are synthesized in a similar fashion from the appropriate intermediate ((R, S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 27 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method I I
1-7.3.1 7.2.1 Br0OO
506/508 0.66 X012_SO1 I 0 0y0 1-7.3.2 7.2.2 415 0.61 X012 SO1 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method \/
N
I I 0 0.0 I-559 0.84 X012 SO1 1-7.3.3 7.2.3 N

H
_____/\ 0 N
I- I 0 0,,,,,0 1-7.3.4 472 0.78 X012_SO1 7.2.4 N
H
\./
N
I- 0 I 0 0y0 1-7.3.5 460 0.74 X012_S01 7.2.5 ,14,,re N
H
---\\/
0 \/

N
1-7.3.6 N 1 0 0y0 559 0.84 X012 SO1 7.2.6 1\11Lr<N7i H

1-7.3.7 N
7.2.7 Br 524/526 0.71 X011 SO2 ,J+1 N
H
F
Intermediate 1-7.3.7 is separated according to method "Chiral SFC F" to give the following compounds of Table 28 Table 28 Educ m/z Intermediat rt Structure [M+H] SEC method (mm) I IC 20 MEOH_NH3.
cr)-N M
7.3.7 Brc H 0õ.õ0 1-7.3.8 H n.d. 2.43 MEOH_NH3.
1-7.3.9 7.3.7 Br., H
j),H 1.94 n.d.

Step 4: Synthesis of Example 7 To 1-7.3 (40 mg, 0.08 mmol) in acetonitrile (1 mL) sodium iodide (14 mg, 0.09 mmol) and chlorotrimethylsilane (12 111_, 0.09 mmol) are added. The mixture is stirred for 20 min. The product is purified by reversed phase HPLC. Yield 39%, m/z 410 [M+H]+, rt 0.96 min, LC-MS Method V018_SO1 For example 58 1-7.3 is stirred in formic acid at 50 C for 10 min in a pressure vessel.
Method C
Synthesis of (1S,2S,4R)-N-11-cyano-2-(1H-indazol-5-ybethy1]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 8) ----)¨ 0 \ N

1-8.1 O
04 0N HN)' N -A-\ N \ N
1-8.2 Example 8 Step 1: Synthesis of Intermediate 1-8.1 To R5 (102 mg, 0.42 mmol) in DMF (3 mL) diisopropylethylamine (296 [tL, 1.70 mmol) and TBTU (136 fig, 0.23 mmol) are added and the reaction mixture is stirred for 15 min. Then R14 (135 mg, 0.42 mmol) is added and the mixture is stirred for additional 1 h.
Water is added to the reaction mixture and extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4 and concentrated. Yield 70%.
1() The following intermediate as shown in Table 29 is synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the amide group):
Table 29 m/z rt LC-MS
Intermediate cduct Structure [M+H]+ (min) method N
0 ,0)1N
1-8.1.1 H2N 428 0.91 R14.1 V011 S01 1-8.1.2 R14.2 437 0.64 X012 SO1 1-8.1.3 R47 H
N-Th-N- NH2 512 1.26 V011 SO1 o'Lo '+' F
'I 'it 1-8.1.4 R49 N NH2 517 1.09 V011 SO1 o"Lo The reaction conditions for 1-8.1.3 and 1-8.1.4 differ: HATU is used instead of TBTU.
Step 2: Synthesis of Intermediate 1-8.2 To 1-8.1 (126 mg, 0.29 mmol) in DCM (1 mL) R2 (155 mg, 0.65 mmol) is added.
The reaction mixture is stirred for 12 hand then concentrated. Yield 100% m/z 310/354/410 [M+H]+, rt 1.02 min, LC-MS Method V012_S01.
The following intermediates as shown in Table 30 are synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):

Table 30 m/z rt LC-MS
Intermediate educt Structure [M+I-1]+ (min) method 1-8.2.1 8.1.1 N n.d. n.d. n.d.

/ N
N

1-8.2.2 N 420 0.70 X012 SO1 8.1.2 N 0 ;(µ1 N

1-8.2.3 494 1.37 V011 SO1 8.1.3 F 0 , H N
(:)".0 1-8.2.4 8.1.4 499 1.22 V011 SO1 H

1-8.2.5 527 0.66 X011_SO3 24.3.2 N
Step 3: Synthesis of Example 8 To 1-8.1 (120 mg, 0.29 mmol) in acetonitrile (7 mL) sodium iodide (132 mg, 0.88 mmol) and chlorotrimethylsilane (106 j.tl, 0.88 mmol) arc added. The mixture is stirred for 12 h, then methanol (7 mL) is added, stirred for 1 h and then concentrated. The residue is dissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated. The product is purified by reversed phase HPLC. Yield 19%, m/z 310 [M+H]+, rt 0.86 min, LC-MS Method VO1 l_S01.
Method D
Synthesis of (1S,2S,4R)-N-[1-cyano-2-(6-oxo-5H-phenanthridin-8-ypethyl]-3-azabicyclo[2.2.1]heptane-2-earboxamide (Example 9) OH
I I 0 0y0 Br I 0 0y0 R16NH, HN

1-9.1 1-7.3.1 Mel HN
)+Lyer:171 I I 0 Example 9 1-9.1.1 õ.11Lel Example 206 Step 1: Synthesis of Intermediate 1-9.1 1-7.3.1 (200 mg, 0.39 mmol) and R16 (65 mg, 0.47 mmol) in acetonitrile (5 mL) is purged with argon. 1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (26 mg, 0.04 mmol) and aq.
sodium carbonate solution (2 mol/L, 395 L) are added and heated to 70 C for 3 h. DCM and water are added to the reaction mixture. The organic layer is dried over MgSO4 and concentrated.
The product is purified by reversed phase HPLC. Yield 50% m./z 487 [M+H]+, rt 0.60 min, LC-MS
Method X012_S01.
to Step 2: Synthesis of Example 9 To 1-9.4 (115 mg, 0.24 mmol) in acetonitrile (5 nit) sodium iodide (106 mg, 0.71 mmol) and chlorotrimethylsilane (90 L, 0.71 mmol) are added. The mixture is stirred for 90 min. The product is purified by reversed phase HPLC. Yield 32%, m/z 387 [M+H]+, rt 0.39 mm, LC-MS Method X012_S01.

Synthesis of Intermediate 1-9.1.1 1-9.1 (100 mg, 0.2 mmol) and Mel (14.2 [IL, 0.23 mmol) are dissolved in 2 mL
DNIF, and NaH
(9.04 mg, 0.23 mmol, as 60% suspension in paraffin oil) is added. After stirring for 12 h at r.t., the mixture is diluted with methanol, filtered and purified by HPLC. The product fractions are freeze-dried to yield 42 mg (41%) 1-9.1.1. mlz 501 [M+H]+, rt 0.65 min, LC-MS Method X012_S01.
Boc deprotection to Example 206 is performed in analogy to the synthesis of Example 9.
Method D1 Synthesis of (1S,2S,4R)-N- [2-(3-chloro-5-methy1-6-oxo-phenanthridin-8-y1)-1 -cyano-ethy1]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 305) \ o ot ,B -B:
Br I I 0 j+LT;1-7.3.1 0 I-18.1(R,S) CI
1-12.1.7 I I 0 CI
,J,Lyer I-18.2(R,S) CI

),LH
.r=

Example 305 Step 1: Synthesis of Intermediate 1-18.1 To 1-7.3.1(4.0 g, 7.9 mmol) in anhydrous dioxane (50 mL) R3 (2.93 g, 11.5 mmol) and potassium acetate (2.27 g, 23.2 mmol) are added. The mixture is purged with argon, [1, l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichlormethan complex (PdC12(dppf)) (0.66 g, 0.81 mmol) is added to the mixture and heated to 70 C overnight. The reaction mixture is diluted with DCM and water. The organic layer is separated, dried and concentrated. The residue is purified by reversed phase HPLC. Yield 71% m/z 554 [M+H]+, rt 0.74 mm, LC-MS Method X011_S03.

The following intermediates as shown in Table 31 are synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 31 m/z LC-MS
Intermediate educt Structure [M+H] rt (mm) method 1-18.1.1 1-7.3.7 1 -572 0.72 X011 SO2 01 o H
1-18.1.2 1-7.3.8 11 )''1317,i 572 0.74 X012 SO1 o o Step 2: Synthesis of Intermediate 1-18.2 To 1-18.1 (150 m g, 0.27 mmol) in anhydrous ACN (5 mL) (5-chloro-2-iodophenyl)methanamine (72.498m g, 0.27 mmol) is added and purged with argon. 1,1 bis(di-tert.butylphosphino)ferrocene to palladium dichloride (17.66 mg, 0.027 mmol) and a solution of sodium carbonate in water 2mol/L
(0.271 mL, 0.54 mmol) ared added, purged again with argon and heated to 70 C
for 6h. The reaction mixture is diluted with DCM and water. The organic layer is separated, dried and concentrated. The crude residue is used for the next step without further purification. Yield 93%
m/z 536[M+H]+, rt 0.71 min, LC-MS Method X012_S01.
The following intermediates as shown in Table 32 are synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 32 m/z Intermediat rt LC-MS
Educt Structure [M+
e (min) method -ft+
NH.
1-18.2.1 1-18.1.1 --,-.
-r------- y 0 - X011 SO
530 0.62 F----.. =--,,------,.--- ----, 1-18.2.2 1-18.1.1 1 N
,F 0-. 0 I '1 0 Y
HN, 7-- ,L,N, 523 0.66 X011 SO
I ¨ N e---' 2 o H,N,i3O
1-18.2.3 1-18.1 ._d- -----0.,..õ0 548 0.48 ..,1s¨j-,_,,, , iEr\i 1-18.1.1 1-18.2.4 1"
-F I\11 0,,õ,. ,0 X011 SO
=( v: ,--1 I 0 ---i 505 0.65 c)1 "

1-18.2.5 1-18.1.1 r 0-*.r,0 X011 SO

523 0.66 Fir.U. N N 2 ir H

m/z Intermediat rt LC-MS
Educt Structure [M+
e (min) method -ft+
1-18.2.6 1-18.1 541 0.69 X012 SO
u_ 2 H 0 ,r-0 HN
O H
1-18.2.7 1-18.1 cr 522 0.65 X012 SO
N
0 0 y0 1 FINõri -1, i HN
1-18.2.8 1-18.1 111 512 0.57 X01250 HN, 11 H ?...."' 1-18.2.9 1-18.1 y - 545 0.61 X011_SO
- .--- 3 il 0 or , o HN
1-18.2.10 1-18.1 F 523 0.68 X01250 ..,,,,.;,--, IN '-,,_ 0 0, ,0 2 F

HN,r, ---õ_, N.,-.=....
H

m/z Intermediat rt LC-MS
Educt Structure [M+
e (min) method -ft+
1-18.2.11 1-18.1 Fi/F
555 0.69 X011 SO
i 3 '---FINL,lorr1.1>
_ 1-18.2.12 1-18.1 F l'I 580 0.60 X011 SO
FICF--%"1 3 N o_ o H
1-18.2.13 1-18.1 NI 526 0.64 X01250 1 _ .---y--,_ -1 i -1-1-18.2.14 1-18.1 ei I 521 0.67 X011 SO
I
0 ----õ,--=
1-18.2.15 1-18.1 JcL 558 0.50 X01250 H I
------"-------0., ,i,..0 HN1 z:-.<õ,...---, -,N '1)N , HH /.......-m/z Intermediat rt LC-MS
Educt Structure [M+
(min) method -ft+
1-18.2.16 1-18.1 111 530 0.54 X011 SO

F
õIL N
N
H

1-18.2.17 1-18.1 505 0.61 X01250 0 ,0 1 F
HN -1-18.2.18 1-18.1 " 512 0.45 X01250 õ...õ 1'1 oyo 1 T
HLN

1-18.2.19 1-18.1 Fl 523 0.62 X012 SO
Hwy 1-18.2.20 1-18.1 545 0.61 X011 SO
O o 3 A "

m/z Intermediat rt LC-MS
Educt Structure [M+
(min) method -ft+
1-18.2.21 1-18.1 o 517 0.61 X011_S0 0 oyo HN N
1-18.2.22 1-18.1 o 565 0.53 X01250 Ho 1-18.2.23 1-18.1 I1 x 602 0.66 X012 SO
HN N, 1-18.2.24 1-18.1.2 505 0.61 X01250 F 0. 0 HN, H

1-18.2.25 1-18.1.2 523 0.63 X01250 F
F 0, 0 HN, m/z Intermediat rt LC-MS
Educt Structure [M+
(min) method H]+
1-18.2.26 1-18.1.2 , 541 0.64 X012 SO
F 0. 0 HN
1-18.2.27 1-18.1.2 548 0.60 X012 SO

F F OyO
HN, 1-18.2.28 1-18.1.2 519 0.67 X012 SO
F o o 1 If H
o 1-18.2.29 1-18.1 570 0.59 X01250 o HN
H

Step 3: Synthesis of Example 305 To 1-18.2 (270 mg, 0.25 mmol) in THE (3 mL) methanesulfonic acid (81.87 1..tL, 1.26 mmol) is added and the reaction mixture is stirred at r.t. overnight. The reaction mixture is concentrated and the residue is purified by reversed phase HPLC. Yield 14% m/z 435 [M+H]+, rt 0.48 min, LC-MS
Method X012 _S01.
Method E

Synthesis of (1S,2S,4R)-N-[1-cyano-2-(6-oxo-5H-phenanthridin-3-ypethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide and (1S,2S,4R)-N41-cyano-2-(6-oxo-5H-phenanthridin-1-ypethyl]-3-azabicyclo12.2.11heptane-2-carboxamide (Example 123 and 128) ''',...------ I 0 ril 0 0y, N, oy, 0 OH

0, *
)4Lii:I>j N,,141 _____________ 1 N N H 2N jiiL
II H H

1-7.3.2 1-10.1 \./
..-------- NI 0 0,,,0 11 0 01__ N N
N NIArel L-o H
H H -31.
1-10.2 / 1-10.3 Si / '=
\/ N

I I N 0 0y0 NJ4iLl H
0 N -1...
-3. L \o H LO
/ 1-10.4 L.) /
Si / 1-10.5 ,5i,, N
N I Irzi_ jiL 0 + HN
I 0 ir<H
-...-Example 123 Example 128 Step 1: Synthesis of Intermediate I-10.1 To 1-7.3.2 (6.0 g, 14.5 mmol) in ethyl acetate (100 mL) tin(II)chloride dihydrate (16.3 g, 72.4 mmol) is added. The reaction mixture is stirred for 12 h. The mixture is set basic with potassium carbonate and aq. sodium hydroxide solution. The organic layer is separated, is dried over MgSO4 and is concentrated. The residue is purified by reversed phase HPLC. Yield 32%
m/z 385 [M+H]+, rt 0.42 min, LC-MS Method X012_S01.
Step 2: Synthesis of Intermediate 1-10.2 To R23 (0.70 g, 2.81 mmol) in DCM (20 mL) diisopropylethylamine (1.20 mL, 7.02 mmol) and HATU (1.09 g, 2.81 mmol) are added and the reaction mixture is stirred for 7 min. Then intermediate 1-10.1 (0.90 g, 2.34 mmol) is added and the mixture is stirred for additional 12 h. The mixture is concentrated and the residue is purified by flash chromatography (cyclohexane/ ethyl to acetate = 70/30). Yield 90% m/z 615 [M+H]+, rt 0.66 min, LC-MS Method X012_S01.
The following intermediate as shown in Table 33 is synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 33 m/z rt LC-MS
Intermediate educt Structure [M+H]+ (min) method Br HN
1-10.2.1 I-10.1 585 /
0.67 X012 S01 J\110 Step 3: Synthesis of Intermediate 1-10.3 To 1-10.2 (800 mg, 1.30 mmol) in DMF (20 mL) sodium hydride (58 mg, 1.43 mmol) is added and the reaction mixture is stirred for 10 min. Then 2-(trimethylsilyl)ethoxymethylchloride (0.25 mL, 1.43 mmol) is added and the mixture is stirred for additional 2 h. Water and DCM is added to the mixture and the organic layer is concentrated. The residue is purified by reversed phase HPLC.
Yield 26% m/z 745 [M+H]+, rt 0.85 min, LC-MS Method X012 501.

The following intermediate as shown in Table 34 is synthesized in a similar fashion from the appropriate intermediate:
Table 34 m/z rt LC-MS
Intermediate Educt Structure [M+H]+ (min) method Br v.N
I-10.3.1 715 /
10.2.1 N 0.84 X012 SO1 si, 17 Step 4: Synthesis of Intermediate 1-10.4 To 1-10.3 (200 mg, 0.27 mmol) in anhydrous DMF (10 mL) tetrakis(triphenylphosphine)palladium (16 mg, 0.01 mmol) and sodium carbonat (58 mg, 0.55 mmol) is added. The reaction mixture is heated to 150 C for 5 h. Water and ethyl acetate is added to the mixture. The organic layer is dried to over MgSO4 and is concentrated. The residue is purified by reversed phase HPLC. Yield 34% in/z 617 [M+H]+, rt 0.84 min, LC-MS Method X012_S0 1.
During this ring cyclization both isomeres are obtained; but it is first possible to separated them by reversed phase HPLC on the last step (see step 6).
ts The following intermediate as shown in Table 35 is synthesized in a similar fashion from the appropriate intermediate:
Table 35 miz rt LC-MS
Intermediate Educt Structure [M+H]+ (min) method I I 0 0y0 1-10.4.1 10.3.1 0 N
635 0.86 X012 SL
Step 5: Synthesis of Intermediate 1-10.5 To 1-10.4 (57 mg, 0.09 mmol) in acetonitrile (5 mL) sodium iodide (42 mg, 0.28 mmol) and chlorotrimethylsilane (35 !IL, 0.28 mmol) are added. The mixture is stirred for 90 min. Then methanol (5 mL) is added and the mixture is stirred for additional 15 min. The mixture is concentrated and DCM and water is added to the residue. The organic layer is separated, is dried over MgSO4 and concentrated again. The crude product is carried on with step 6. Yield >95%, m/z 517 [M+H]+, rt 0.62 min, LC-MS Method X012_SO1.
Step 6: Synthesis of Example 123 and 128 1-10.5 (48 mg, 0.09 mmol) is stirred in formic acid for 48 h. The mixture is purified by reversed phase HPLC. It is possible to separate the both isomers:
Isomer 1 = example 123: yield 3%, m/z 387 [M+H]+, rt 0.38 min, LC-MS Method X012_S01, Isomer 2 = example 128: yield 6%, m/z 387 [M+H]+, rt 0.35 min, LC-MS Method X012_SO1.
Method W
Synthesis of (1S,2S,4R)-N-1(1S)-1-cyano-242-fluoro-4-[(1-methyl-4-piperidyl)oxy[phenyl]ethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 319) N F Br ,,,N1 N

141111 ____________________________ 1.

1-2.2 ?-j1P1 N ENIIN
H , ----7. 0 -)\
Example 319 ====-.N, I
Step 1: Synthesis of Intermediate I-19.1 1-2.2 (300 m g, 0.64 mmol) in anhydrous toluene is purged with argon. 4-hydroxy-1-methylpiperidinc (148.18 mg, 1.29 mmol), allylpalladium chloride dimcr (5.88 mg, 0.016 mmol), 2-(di-t-butylphosphino)-3-methoxy-6-methy1-2'-4'-6'-tri-i-propy1-1,1'-biphenyl (18.09 mg, 0.039 mmol), cesium carbonate (314.4 mg, 0.965 mmol) and molecular sieve (4A) are added and purged with argon again. The reaction mixture is stirred at 90 C for 21h. Afterwards filtered through a pad of celite, washed with ethyl acetate and concentrated. The crude residue is purified by reversed to phase HPLC and freeze dried. Yield 16%.
Step 2: Synthesis of Example 319 (see method A2, Step 4) To 1-19.1(50 m g, 0.1 mmol) in acetonitrile (6 mL) sodium iodide (45 mg, 0.3 mmol) and chlorotrimethylsilane (38.1 L, 0.3 mmol) are added. The mixture is stirred for 2 h, then methanol is added, stirred for additional 30 min and then concentrated. The residue is purified by reversed phase HPLC. Yield 34%, nz/z 401 [M+H]+, A 0.31 min, LC-MS Method X012_S02.
Method W1 Synthesis of (1S,2S,4R)-N-1(1S)-1-cyano-2-[4-[3-(dimethylamino)-1-piperidy1]-2-fluoro-phenylIethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 344) eH / N
0 0 _________________________________ 3 -'-*' 1-2.2 F Br >,0 F N--0 1-20.1 e i I.
F N
Y
Example 344 Step 1: Synthesis of Intermediate 1-20.1 To 1-2.2 (300 mg, 0.64 mmol) in anhydrous dioxane (8 mL) are added 3-dimethylamino-piperidine (164.96 mg, 1.29 mmol) and cesium carbonate (846.87 mg, 2.57 mmol). The mixture is purged to with argon and chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propy1-1,1'-bipheny1)[2-(2-aminoethypphenyl]palladium(II) (95.05 mg, 0.13 mmol) is added and stirred at 90 C for 2h. The reaction mixture is filtered and concentrated. The residue is diluted with dichlormethane and water.
The organic layer is separated, dried and concentrated. The crude product is purified by reversed phase HPLC. Yield 12%.
Step 2: Synthesis of Example 344 (see method A5, Step 3) To 1-20.1(53 mg, 0.1 mmol) in acetonitrile (8 mL) p-toluenesulfonic acid monohydrate (68.70 mg, zo 0.36 mmol) is added and stirred at r.t. for 6h.. The mixture is concentrated, diluted with methanol and purified by reversed phase HPLC. Yield 28%, m/z 414 [M+H]+, A 0.74 min, LC-MS Method 004_CA05.

Method Z
Synthesis of (1S,25,4R)-N-I1-cyano-2-(3-fluorophenanthridin-8-ypethyl]-3-azabicyclo[2.2.1]heptane-2-carboxamide (Example 315) Nrc:i&irH 1;1?1,r,H

HO
I-18.1(R,S) 0 0 I-21.1(R,S) NH, =L I I

HO
I-21.2(R,S) N

I-21.3(R,S) 1\1 I I
Example 315 Step 1: Synthesis of Intermediate 1-21.1 To _18.1 (1.5 g, 2.7 mmol) in anhydrous THF (1 inL) under argon atmosphere lithium borhydride (59m g, 2.7 mmol) is added. The mixture is heated to 50 C
overnight. The reaction .. mixture is carefully diluted with water and extracted with ethyl acetate.
The organic layer is separated, dried and concentrated. The crude residue is filtered through a pad of silica gel (cyclohexane/ ethyl acetate 1:2). Yield 37%.
m Step 2: Synthesis of Intermediate 1-21.2 To 1-21.1 (260 m g, 0.495 mmol) in anhydrous ACN (5 mL) 5-fluoro-2-iodo-aniline (117.28m g, 0.495 mmol), 1,1 bis(diphenylphosphino)ferrocene palladium dichloride (36.21 mg, 0.049mmo1) and a solution of sodium carbonate in water 2mo1/L (0.742 mL, 1.48 mmol) are added and purged with argon and heated to 80 C for lh. The reaction mixture is diluted with DCM
and water. The organic layer is separated, dried and concentrated. The crude residue is purified by reversed phase HPLC. Yield 41%, miz 509[M+H]+, rt 0.66 min, LC-MS Method X01 1_S03.
The following intermediate as shown in Table 36 is synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile .. group):
Table 36 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method N OH
I-21.2.1 1-21.1 - o X011 S
o 0 1\11-12 491 0.63 Step 3: Synthesis of Intermediate 1-21.3 To 1-21.2 (103mg, 0.2mmo1) in DCM manganese(IV)oxide (153.65 mg, 8.73mmo1) is added under cooling. The reaction mixture is stirred at r.t. overnight and lh at 50 C.
Another manganese(IV)oxide (50 mg, 2.84mmo1) is added and stirred for further 2h at 50 C. The reaction mixture is filtered through a pad of cellulose and concentrated in vacuo. The residue is purified by reversed phase HPLC.
Yield 27%.
The following intermediate as shown in Table 37 is synthesized in a similar fashion from the appropriate intermediate ((R,S) =1:1 mixture of stereoisomers at the carbon adjacent to the nitrile group):
Table 37 m/z LC-MS
Intermediate Educt Structure of Intermediate rt (min) [M+H]+ method N N
I-21.3.1 I-21.2.1 o o'o N n.d. n.d. n.d.
Step 4: Synthesis of Example 315 To 1-21.3 (26.4 mg, 0.054 mmol) in acetonitrile, p-toluenesulfonic acid monohydrate (35.98 mg, 0.189mmol) is added and stirred for 5 h. The reaction solution is purified by reversed phase HPLC.
Yield 60%, m/z 389 [M+H]+, rt 0.37min, LC-MS Method X12 _S01.
Synthesis of starting materials/ educts Synthesis of tert-butyl N-1(1S)-2-amino-1-[(4-bromo-2-fluoro-phenyl)methyl]-2-oxo-ethyl]carbamate (R1) Br H2N ,,,, H2N N "
Br F F

Br Br Br 1-11.1 1-11.2 1-11.3 >o OOH

Br Br 1-11.4 Step 1: Synthesis of Intermediate I-11.1 R24 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to -78 C.
Then n-butyllithium (2.5 Mm hexanes, 552 mL, 1381 mmol) is added dropwise, keeping the temperature below -78 C.
After 30 min R25 (324g, 1209 mmol) in tertahydrofurane (dry) (120 mL) is added dropwise. The reaction mixture is stirred at -78 C for 1 h. The mixture is quenched with saturated NH4C1 solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue is purified by flash chromatography (heptane/ ethyl it) acetate = 80/20). Yield 60%.
Step 2: Synthesis of Intermediate 1-11.2 To 1-11.1 (104 g, 265 mmol) in acetonitrile (600 mL) aq. 0.2 M HC1 (2788 mL, 558 mmol) is added.
The mixture is stirred at RT for 12 h. The mixture is extracted with diethylether and the pH of the aq. layer is adjusted to ¨8 with sat. NaHCO3-solution. Then it is extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4and concentrated. Yield 80%.
Step 3: Synthesis of Intermediate 1-11.3 1-11.2 (62.4 g, 211 mmol) is stirred in aq. 3 M HC1 (3 mon, 1000 mL) at 60 C
for 16 h. The mixture is cooled down and the pH is adjusted to ¨7 with aq. 6 M NaOH. Then the reaction mixture is filtered, washed three times with water and dried in a vacuum oven at 40 C for 12 h.
Yield 74%.
Step 4: Synthesis of Intermediate 1-11.4 To 1-11.3 (151g, 546 mmol) in 1,4-dioxane (2.2 L) is added aq. 2 M sodium carbonate (301 mL) and di-tertbutyl dicarbonatc (138 g, 147 mL). The mixture is stirred for 4h.
Then water is added and the pH is adjusted to ¨4-5 with citric acid. The mixture is extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4and concentrated. The residue is stirred in heptane for 15 mm and the product is filtered off Yield 87%.
Step 5: Synthesis of RI
To 1-11.4 (181 g, 476 mmol) in dry DMF (1200 mL) N-methylmorpholine (72 g, 713 mmol) and TBTU (153 g, 476 mmol) are added and the reaction mixture is stirred for 30 min. Then the reaction mixture is cooled to 0 C and aq. 35% ammonium chloride solution (47 mL, 856 mmol) is added and the mixture is stirred at room temperature for 12 h. Water is added and the formed product is filtered off and washed three times with water. The product is dried in a vacuum oven at 40 C for 72 h. Yield 64%.
The following intermediate as shown in Table 38 is synthesized in a similar fashion from the appropriate intermediates:
Table 38 Intermediate Structure m/z [M+H]+ rt (min) LC-MS method H (13 R1.1 y NH, 0 409 1.05 VOi i_SOi 0 N..,====, 217 [M+H-R1.2 0.69 Z018 SO4 BOC]+
OH

Synthesis of (1S,25,4R)-3-[(tert.-butoxy)carbony1]-3-azabicyclo[2.2.11heptane-2-carboxylate (R5) The compound is commercially available or can be synthesized in analogy to Tararov et al, Tetrahedron Asymmetry 13 (2002), 25-28.
=0 31.

___________________________________________________________ 31.

e0 0 -311.
0, Step 1: Synthesis of R5C

A solution of RSA (44.9g, 0.44 mol), freshly distilled from a commercially available solution in toluene (at 50mbar, 55 C) in diethylether (300 ml) is cooled at -10 C, followed by dropwise addition of R5B (53 g, 440 mmol), keeping the temperature below 0 C. After complete addition, MgSO4*H20 (91g, 660 mmol) is added, and the resulting mixture stirred at room temperature overnight. The mixture is filtrated, the solution phase concentrated in vacuo and the residue destilled under reduced pressure to yield R5C (47g, m/z 206 [M+H]+, rt 1.29 min, LC-MS Method V003_003). The product is used without further purification.
Step 2: A solution of R5C (47g; 229 mmol) and R5D (30g; 458 mmol) (freshly distilled from dicyclopentadien) in DMF (150 ml) and 120 1 water is cooled to 0 C, before TFA
(18 ml; 234 mmol) is added dropwise. The mixture is stirred overnight at room temperature, then added to a solution of 40g NaHCO3 in 1200 ml water and extracted with diethylether. The organic layer is separated, washed subsequently with aqueous NaHCO3 and water, dried over MgSO4, and concentrated in vacuo. The residue is worked up by column chromatography on silica (cyclohexane/ethyl acetate = 9:1) to yield R5E (Yield 52% nilz 272 [M+H]+, rt 0.42 min, LC-MS
Method X001_004) Step3:To a solution of R5E (24.8 g, 91 mmol) in ethanol (250 ml), Raney-nickel is added (2.5 g) and reacted at 50 psi under a hydrogen atmosphere at room temperature. The catalyst is filtered of, the solution concentrated in vacuo and the residue worked up by chromatography on silica (cyclohexaneiethyl acetate 9:1). After evaporation of the organic solvent, the obtained product is redissolved in diethylether and triturated with solution of HC1 in dioxanc, concentrated in vacuo, redissolved in 200 ml ethanol and concentrated in vacuo to yield R5F: (Yield 78% m/z 274 [M+H]+, rt 0.42 min, LC-MS Method X001_004).
Step4: To a solution of R5F (22 g, 71 mmol) in ethanol (250 ml), 10% Pd/C is added (2.5 g) and reacted at 15 bar under a hydrogen atmosphere at room temperature. The catalyst is filtered of, the solution concentrated in vacuo. The residue is washed with diisopropylether to yield R5G. (Yield 98% m/z 170 [M+H]+, rt 0.48 min, LC-MS Method V001_007).
Step5: To R5G in a solution of triethylamin (24.6 ml), THF (150 ml) and water (2m1), R51 (15.9 g;
73 mmol) is added and the resulting mixture stirred for 40hours at room temperature, then concentrated in vacuo. Ethyl acetate is added to the residue, subsequently extracted with water, 1 N

acidic acid and water, before the organic layer is dired over MgSO4 and concentrated in vacuo to yield R51. (Yield 95% rez 270 [M+H]+, rt 1.33 min, LC-MS Method V003_003).
Step6: A mixture of R51 (16.9 g; 63 mmol) in acetone (152 ml), water (50 ml) and lithium hydroxide (3g, 126 mmol) is stirred overnight at room temperature. Water (100m1) was added, the volumn reduced in vacuo before cooling to 0 C followed by the addition of 1N
aqueos HCl to acidify to a pH of 2-3, immediately followed by extraction with ethyl acetate.
The organic layer was washed with water, dried (MgSO4) and concentrated. To the residue, dichloromethane (100 ml) and cyclohexane (100m1) was added, the volumn reduced in vacuo by half and the mixture temperated at 15 C. The precipitate was filtered of, washed with cyclohexane to yield R5 (Yield 66%, in/z 242 [M+H]+).
Synthesis of (2S)-2-amino-3-(4-bromo-2-fluoro-phenyl)propanamide (R6) OyN.,!.,.1., 2 \x 0 is II NI
Br Br To R1 (10.0 g, 27.7 mmol) in DCM (70 mL) TFA (25 mL, 162.0 mmol) is added and the reaction mixture is stirred for 12 h. Then the reaction mixture is concentrated, the residue is dissolved in DCM and diisopropylether is added. The product precipitates and is filtered by suction and washed with diisopropylether. Yield >95% nilz 261 [M+H]+, rt 0.67 min, LC-MS Method V018_S01.
The following intermediate as shown in Table 38.1 is synthesized in a similar fashion from the appropriate intermediates:
Table 38.1 Intermediate Structure m/z [M+H]+ rt (min) LC-MS method R6.1 z 217 0.08 Z011_S03 OH
For R6.1 the reaction time is 2h. After the reaction mixture is concentrated, the crude residue is freeze-dried and used without further purification for the next step.
Synthesis of 2-Amino-3-(1H-indazol-5-Apropanamide (R14) y 0 oõ
0 0y HWY-L o .'0 O-P=0o NHo NH
0 \ N /
0, R22 N
\ N

1-8.4 1-8.3 0,0 0 y NH

___________________________________________ 3 N
\ N \ N

1-8.5 -8.6 Step 1: Synthesis of Intermediate 1-8.3 1,1,3,3,-Tetramethylguanidin (0.44 mL, 3.51 mmol) in THF (5mL) is cooled down to -70 C. Educt R22 (1.00 g, 3.36 mmol) is dissolved in 5 mL THF and is added. The mixture is stirred for 5 min before R15 (0.49 g, 3.36 mmol) ¨ also dissolved in 5 mL THF ¨ is added dropwise. The cooling is removed and the mixture warms up to room temperature. The reaction mixture is heated to 80 C
for 12 h. Because of remaining educt Tetramethylguanidin and R22 are added twice and the mixture is stirred at 80 C for additional 4 h. The reaction mixture is concentrated. Ethyl acetate and water are added to the residue. 1 M sulfuric acid is added and the organic layer is separated, is dried over MgSO4 and concentrated. Yield 87%, m/z 318 [M+H]+, rt 0.97 min, LC-MS Method V011_SOL
The following intermediate as shown in Table 39 is synthesized in a similar fashion from the appropriate intermediate:
Table 39 LC-MS
Intermediate Structure m/z [M+H]+ rt (min) method ,= 0 1-8.3.1 10 0 NH 318 1.00 V012 SO1 / N
Step 2: Synthesis of Intermediate 1-8.4 To 1-8.3 (925 mg, 2.91 mmol) in methanol (30 mL) Pd/C (10%, 130 mg) is added.
The reaction mixture is stirred under hydrogen (3 bar) for 16 h. Then the mixture is filtered and the filtrate is concentrated. The residue is triturated with diethyl ether and the product is filtered by suction.
Yield 88%, m/z 320 [M+H]+, rt 0.99 min, LC-MS Method V01 1S01.
The following intermediate as shown in Table 40 is synthesized in a similar fashion from the appropriate intermediate:
Table 40 m/z LC-MS
Intermediate Educt Structure of Intermediate rt (min) [M+H]+ method 1-8.4.1 1-8.3.1 NH 320 0.96 V011 SO1 / N
Step 3: Synthesis of Intermediate 1-8.5 To 1-8.4 (820 mg, 2.57 mmol) in methanol (15 mL) sodium hydroxide solution (2.5 mL, lmol/L) is added. The reaction mixture is heated to 40 C for 2 h. The mixture is concentrated partially and 1 M HC1 is added to neutralization. The precipitation is filtered with suction, is dissolved in methanol and concentrated quickly. Yield 65%, tn/z 306 [M+H]+, rt 0.57 min, LC-MS
Method VOI l_S01.
The following intermediate as shown in Table 41 is synthesized in a similar fashion from the appropriate intermediate:
io Table 41 m/z LC-MS
Intermediate educt Structure rt (min) [M+1-1]+ method o I-8.5.1 I-8.4.1 NH
HO 306 0.55 Vol 1 SO1 / N
Step 4: Synthesis of Intermediate 1-8.6 To 1-8.5 (400 mg, 1.31 mmol) in DMF (5 mL) diisopropylethylamine (502 jiL, 2.88 mmol) and is TBTU (421 mg, 1.31 mmol) are added and the reaction mixture is stirred for 15 min. Then aq. 30%
ammonia solution (545 [IL, 9.61 mmol) is added and the mixture is stirred for additional 12 h.
Water is added to the reaction mixture and extracted with ethyl acetate. The organic layer is washed with brine and saturated NaHCO3 solution, is dried over MgSO4 and concentrated. Yield 55%, m/z 305 [M+H]+, rt 0.75 min, LC-MS Method VO 1 1_S01.

The following intermediate as shown in Table 42 is synthesized in a similar fashion from the appropriate intermediate:
Table 42 rt Intermediat m/z LC-MS
Educt Structure of Intermediate (min [M+H]+ method 1-8.6.1 1-8.5.1 NH V011 SO
H2N [M+Na] 0.77 / N

commerciall 1-8.6.2 315 n.d. n.d.
y available For 1-8.6.2 N-methylmorpholine is used instead of diisopropylethylamine (in analogy to synthesis of R1) Step 5: Synthesis of R14 To 1-8.6 (130 mg, 0.43 mmol) in DCM (3 mL) TFA (358 ittL, 0.47 mmol) is added and the reaction mixture is heated to 30 C for 12 h. Then the reaction mixture is concentrated. Yield >95%.
The following intermediate as shown in Table 43 is synthesized in a similar fashion from the appropriate intermediate:
Table 43 Intermediate Educt Structure of Intermediate m/z rt LC-MS

[M+H]+ (min) method R14.1 1-8.6.1 H2 N 227 0.53 VO1 1 SO1 [M+Na1+

R14.2 1-8.6.2 z 214 0.31 X012 SO1 Synthesis of 5-bromo-2-methyl-isoindoline (R4) CIH
N¨

O NH _____________________ Br Br CIH

The pH of a mixture of R26 (1.85 g, 7.9 mmol) in methanol (100 mL) and water (10 mL) is adjusted to ¨5 with acetic acid. Then a 37% fonnalin solution (1.28 mL, 15.8 mmol) is added and the mixture is stirred for 15 min. Sodium cyanoborohydride (0.74 g, 11.8 mmol) is added and the reaction mixture is stirred for additional 12 h. The mixture is concentrated and ethyl acetate and aq.
to 1 M NaOH solution are added to the residue. The organic layer is washed with NaCl solution, dried over MgSO4 and concentrated. The residue is dissolved in diethyl ether and ethereal HC1 is added dropwise. The resulting precipitate is filtered off. Yield 62% m/z 212/214 [M+H]+, rt 0.65 min, LC-MS Method V012 _S01.
Synthesis of 1-(4-bromo-benzenesulfony1)-4--methyl-piperazine (R34) \\ \\
S, CI N
Br Br R33 (800 mg, 3.1 mmol) is dissolved in DCM, N-methyl-piperazine (313 mg, 3.1 mmol) is added and stirred for 12 h. After addition of 2 mL IN HCl under stirring the phases are separated. The organic phase is dried over MgSO4 and after filtration evaporated in vacuo.
Yield:84 % miz 319 (M+H)+.
The following intermediates as shown in Table 44 are synthesized in a similar fashion from the appropriate intermediate:
Table 44 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method \\
R34.1 R33 304 n.d. n.d.
.\/
Br \\
S, R34.2 R33 306 n.d. n.d.
Br R34.3 R33 0 / 340 0.64 X012_SO1 Br ¨ F F
I I \

R34.4 Br 337/339 0.36 X012_SO1 S

R34.5 R33 0 333/335 0.36 X012 S01 Br S¨N
II rTh II

For R34.4 and R34.5 additional 2eq. of DIPEA are added to the reaction mixture.
Synthesis of Reagent R37 S I I

N
Br Br Br Step 1: Synthesis of R36 R35 (200 )tt, 1.448 mmol) is dissolved in 10 mL methanol. Cyanamide (79.112 mg, 1.882 mmol), to potassium tert-butoxide (194.9 mg, 1.737 mmol) and N-bromosuccinimide (386.282 mg, 2.171 mmol) are added and stirred for 1 h at room temperature. The product is purified by preparative HPLC (Waters 30x100 mm, 10 gm, sunfire RP18, acetonitrile/water/TFA). The fractions containing the product are combined and and lyophilized. Yield 87%, m/z 244 [M+H]+, rt 0.62 min, LC-MS Method Z018_SO4.
In analogy the following reagent as shown in Table 45 is prepared:
Table 45 m/z rt LC-MS
Intermediate Educt Structure [M+H]+ (min) method R36.1 commercially 243 0.64 Z018 SO4 available Br-Step 2: Synthesis of R37 R36 (335 mg, 1.378 mmol) is dissolved in 3 ml. ethanol. Potassium carbonate (571.315 mg, 4.134 namol) and 3-chloroperbenzoic acid (356.696 mg, 2.067 mmol) are added at 0 C, and the mixture is stirred for 2 h at room temperature. The solvent is evaporated in vacuo and the residue is dissolved in DMF. The product is purified by preparative HPLC (Waters 30x100 mm, 10 i.tm, sunfirc RP18, acctonitrileiwater/TFA). The fractions containing the product arc combined and and lyophilized. Yield 71%, m/z 260 [M+H]+, rt 0.68 min, LC-MS Method Z018_SO4.
In analogy the following reagent as shown in Table 46 is prepared:
Table 46 m/z rt LC-MS
Intermediate Educt Structure of Intermediate [M+H]+ (min) method R37.1 R36.1 259 0.67 Z011 SO3 Br ---Ort Synthesis of I- [3I4-(bromomethyl)-3-fluoro-pheny1]-5-methyl-pyrazol-1-yl]ethanone (R13) R28 1-13.1 \O \O
N¨N N¨N
I / I / /
-7.
Br 1-13.2 1-13.3 R13 Step 1: Synthesis of Intermediate I-13.1 To potassium tert.-butylate (7.4 g, 65.6 mmol) in anhydrous THF (300 mL) is added crown ether 18-6 (12.2 g, 46.0 mmol). The mixture is cooled down to 0 C and R28 (5.0 g, 32.9 mmol) is added and stirred for 15 min at room temperature. Then acetic acid methyl ester (5.2 mL 65.7 mmol) is added and the reaction mixture is stirred for additional 1 h. The mixture is concentrated and the residue is purified via flash chromatography (cyclohexane / ethyl acetate =
95:5). Yield 79%, m/z 195 [M+H]+, rt 0.66 min, LC-MS Method V01 1_S01.
Step 2: Synthesis of Intermediate 1-13.2 To 1-13.1 (5.1 g, 26.1 mmol) 1 M hydrazine solution in THF (78.2 mL, 78.2 mmol) is added and the reaction mixture is heated to 80 C for 12 h. The reaction mixture is concentrated and the residue is purified via flash chromatography (cyclohexane / ethyl acetate =
70:30). Yield 90%, m/z 191 [M+H]+, rt 1.01 min, LC-MS Method V011_SOL
Step 3: Synthesis of Intermediate 1-13.3 1-13.2 (1.00 g, 5.3 mmol) and acetic acid anhydride (5.00 mL, 53.0 mmol) are stirred for 12 h.
Water and methanol are added to the reaction mixture, the precipitate is filtered by suction and dried in vacuo. Yield 87%, m/z 233 [M+H]+, rt 1.31 min, LC-MS Method VO 1 ISO
1.
Step 4: Synthesis of R13 To 1-13.3 (0.95 g, 4.1 mmol) in DCM (25 mL) is added N-bromo succinimide (0.80g. 4.5 mmol) and 2,2'-azobis(isobutyronitrile) (50 mg). The reaction mixture is refluxed for 12 h under radiation with an Hg lamp. The mixture is concentrated and the residue is purified via flash chromatography (cyclohexane / DCM = 75:25). Yield 39%, rn/z 311 [M+H]+, rt 1.43 min, LC-MS
Method V018_SOL
Synthesis of 6-bromo-2-methyl-3,4-dihydroisoquinolin-1-one (R32) NH
BrXXtBr R31 (500 mg, 2.2 mmol) in DMF (3 mL) is cooled down to 0 C. Under argon atmosphere NaH
(60%, 121 mg, 3.0 mmol) is added and stirred for 20 min. Then methyl iodide (0.275 mL, 4.4 mmol) is added and the mixture is stirred for additional 1 h at 0 C. Ice water is added to the reaction mixture and the precipitate is filtered by suction and dried at 50 C
in the vacuum oven for 12 h. Yield 73%, mk 240/242 [M+H]+, rt 0.89 min, LC-MS Method V012_S01.
Synthesis of tert-butyl 2-(bromomethyl)-9H-carbazole-9-carboxylate (R13.1 for synthesis of!-7.1.3) 0 Br 0 O.
R38 1-15.1 1-15.2 R13.1 Step 1: Synthesis of Intermediate 1-15.1 3-Methyl-diphenylamine R38 (1.0 g, 5.5 mmol), K2CO3(75 mg, 0.55 mmol) and palladium acetate .. (37 mg, 0.16 mmol) in 2,2-dimethyl-1-propanol (5 mL) is is stirred at 110 C for 14 h. Water is added to the reaction mixture and extracted with dichloromethane. The combined organic layer is concentrated in vacuo, residue triturated with methanol/dichloromethane and dried in vacuo and directly taken to the next step. Yield 29%, m/z 182 [M+H]+, rt 0.67 min, LC-MS
Method X012_S01.
Step 2: Synthesis of Intermediate 1-15.2 I-15.1 (285 mg, 1.6 mmol), di-tert.-butyl dicarbonatc (412 mg, 1.9 mmol) and DMAP (50 mg, 0.41 mmol) in dichloromethane (10 ml) are stirred at room temperature for 16 hours.
The reaction mixture extracted with water, the organic layer is separated and concentrated in vacuo and directly taken to the next step. Yield 86%, nilz 282 [M+H]+, rt 0.89 min, LC-MS Method X012_S01.
Step 3: Synthesis of Intermediate R13.1 1-15.2 (380 mg, 1.4 mmol), N-bromosuccinimide (289 mg, 1.6 mmol), AIBN (20 mg, 0.12 mmol) in tetrachloromethane (5 mL) is heated to reflux over 16 h. Water and dichloromethane are added to the reaction mixture, the organic layer separated and concentrated. The residue is triturated with methanol and used directly in the next step. Yield 41%, m/z 360 [M+H]+, rt 0.67 min, LC-MS
Method VO11_S01.
Synthesis of tert-butyl 3-(chloromethyl)-9H-carbazole-9-carboxylat (R13.2 for synthesis of 1-7.1.6) OH
R39 1-16.1 1-16.2 0* 0 HO CI
1-16.3 R13.2 Step 1: Synthesis of Intermediate 1-16.1 to 9H-Carbazole-3-carboxylic acid R39 (500 mg, 2.4 mmol), in methanol (20 mL) is cooled to 0 C.
Thionylchloride (206 ml, 2.8 mmol) is added dropwise to the stirred mixture at this temperature.
The mixture is then stirred at room temperature for 16 hours. The formed precipitate is filtered and dried in vacuo and directly taken to the next step. Yield 53%, m/z 226 [M+H]+, rt 0.59 min, LC-MS Method X012_S01.
Step 2: Synthesis of Intermediate 1-16.2 1-16.1 (280 mg, 1.2 mmol), di-tert.-butyl dicarbonate (326 mg, 1.5 mmol) and DMAP (50 mg, 0.41 mmol) in dichloromethane (10 ml) are stirred at room temperature for 16 hours.
The reaction mixture extracted with water, the organic layer is separated and concentrated in vacuo and directly taken to the next step. Yield 99%, m/z 326 [M+H]+, rt 0.84 min, LC-MS Method X012_SOI.

Step 3: Synthesis of Intermediate 1-16.3 1-16.2 (400 mg, 1.2 mmol) and boronhydride-tetrahydrofuran addukt (1,2 ml 1M
in THF, 1.2 mmol) are dissolved in THF (5m1). LiBH4 is repeatedly added in small portions at 50 C, until .. HPLC shows completion of reaction. Water and dichloromethane are added to the reaction mixture, the organic layer separated, concentrated.and purified via HPLC. Yield 40%, nilz 280 [M-H20+H]+, rt 0.70 min, LC-MS Method X012_S01.
Step 4: Synthesis of Intermediate RI3.2 1-16.3 (145 mg, 0.5 mmol) and DIPEA (171 I, 1.0 mmol) are dissoleced in dichloromethane (10 ml) and cooled to -10 C. Methanesulfonylchloride (46 1, 0.6 mmol) in dichloromethane (1 ml) is added dropwise. After complete addition, the mixture is stirred for 16 h at room temperature. Water is added to the reaction mixture, the organic layer separated, concentrated in vacuo to yield R13.2, which is directly taken to the next step. Yield 73%, rt 0.87 min, LC-MS Method X012_S01.
Synthesis of 2-(chloromethyl)-9,10-dihydrophenanthrene (R13.3 for synthesis of 1-7.1.4) H
R40 1-17.1 HO CI
1-17.2 R13.3 Step 1: Synthesis of Intermediate 1-17.1 zo .. 2-Acetyl-9,10-dihydro-phenanthren R40 (1.0 g, 4.5 mmol) is added to solution of bromine (924.7 I, 18 mmol) and KOH (3.3 g, 58.5 mmol) in water (20 ml) at 0 C. After addition is completed, the reaction mixture is heated to 55 C for 16 hours. The mixture is cooled to r.t., extracted with dichloromethane. The aqueous phase is separated, acidified with 1 M HC1 aq and the precipitating product is filtered off and dried in vacuo at 50 C. Yield 92%, m/z 225 [M+H]+, rt 0.62 min, LC-MS Method X012_SOI.

Step 2: Synthesis of Intermediate 1-17.2 I-17.1 (930 mg, 4.2 mmol) is dissolved in THF (10 ml), CDT (874 mg, 5.4 mmol) is added in small portions and the mixture is stirred for 1 h at 50 C. The mixture is added slowly to sodium .. borohydride (470 mg, 12.4 mmol) in ice water, so that the temperature remains below 10 C. The mixture is stirred for 16 hours at r.t. and extracted with dichloromethanewater. The organic layer is separated and concentrated in vacuo, the remaining crude product purified via HPLC. Yield 53%, m/z 210 [M]+, 193 [M-H20]+, rt 0.61 min, LC-MS Method X012_S01.
m Step 3: Synthesis of Intermediate R13.3 1-17.2 (460 mg, 2.2 mmol), DIPEA (766 I, 4.4 mmol) are dissoleced in dichloromethane (10 ml) and cooled to -10 C. Methanesulfonylchloride (207 I, 2.6 mmol) in dichloromethane (1 ml) is added dropwise. After complete addition, the mixture is stirred for 16 h at room temperature. Water is added to the reaction mixture, the organic layer separated, concentrated in vacuo and the remaining crude product purified via HPLC. Yield 67%, m/z 228 [M]+, rt 0.79 min, LC-MS
Method X012_S01.
Synthesis of 6-Aza-tricyclo[3.2.1.0*2,4*]octane-6,7-dicarboxy1ic acid 6-tert-butylester (R6.2) 0) 0 p.
yo o <CriLOH
Ny0 <C1r-jµLO0 R6.1 1-14.1 Step 1: Synthesis of Intermediate R29.2 Dicyclopenta-1,3-diene is cracked and distilled at 42 C and 1013 mbar to give cyclopenta-1,3-diene.
Ethyl 2-oxoacetate is also freshly distilled from a commercially available solution in toluene.
Assumed concentration is 50%.
To N-boc-imino-(triphenyl)phosphorane (11.32 g, 30.00 mmol) in toluene (100mL) is added ethyl 2-oxoacetate (15mL, 60.00 mmol) and cyclopenta-1,3-diene (5 mL, 60.00 mmol) and stirred overnight at r.t.. The reaction mixture is concentrated and the crude residue is purified over silica gel (cyclohexanei ethyl acetate 7:3). Yield 16%
R29.2. can be obtained through preparative chiral chromatography from this mixture of R29.1 and R29.2 (table 46.1)using method Chiral SFC G .
Table 46.1 Intermediate Structure of Intermediate R29.1 0 ¨\
R29.2 N 0 Step 2: Synthesis of Intermediate I-14.1 To R29.2 (5.00 g, 18.7 mmol) in diethylether (100 mL) is added palladium(II) acetate (0.42 g, 1.87 mmol). Under stirring diazomethane solution in diethylether (62 mmol) is added. The reaction mixture is stirred for 12 h. To destroy remaining diazomethane, silica gel and 3 mL acetic acid are added. Then the mixture is stirred for additional 1 h and filtrated. The solution is concentrated and extracted with DCM, water and brine. Yield 98%, m/z 226 [M+H-tButyl]+, rt 0.64 min, LC-MS
Method X012_S01.
Step 3: Synthesis of R6.2 To 1-14.1 (5.40 g, 19.2 mmol) in dioxane (60 mL) is added aq. 4 M NaOH (20 mL, 80 mmol). The reaction mixture is heated to 50 C for 3 h. The mixture is extracted two times with DCM, then the water layer neutralized with 2 M HC1 and extracted three times with DCM. The combined organic layers are dried over MgSO4 and concentrated. The residue is dissolved in diethylether and evaporated, the product crystallizes. Yield 88%, nilz 198 [M+H-tButyl]+, rt 0.48 min, LC-MS
Method X012_S01.
Synthesis of 1-Methyl-6-(4, 4, 5, 5-tetramethyl-[1, 3, 21dioxaborolan-2-y1)-1, 3-dihydro-indol-2-one (R7) Br Br R27 0 1-12.1 0 Br R3 1-12.2 R7 Step 1: Synthesis of Intermediate 1-12.1 To R27 (25.0 g, 111 mmol) in acetonitrile (750 mL) is added Mel (15 mL, 241 mmol) and K2CO3 (60.0 g, 434 mmol) and the reaction mixture is stirred at 60 'V for 2 h. The reaction mixture is filtered and concentrated. Water and ethyl acetate are added to the residue.
The organic layer is extracted twice with water, dried over MgSO4 and concentrated. Yield 56%, nviz 240/242 [M+1-1] , rt 0.48 min, LC-MS Method X001_004.
The following intermediates as shown in Table 47 are synthesized in a similar fashion from the appropriate intermediates:
Table 47 Intermediate Structure m/z [M+H]+ rt (min) LC-MS
method 1-12.1.1 311/313 0.362 Z020 SO1 ri , 1-12.1.2 rd'N- n.d. n.d. n.d.
Br, 1-12.1.3 N 211/213 0.55 X012 SO1 Br 1-12.1.4 r!, n.d. n.d. n.d.
-1-12.1.5 245 0.21 X012 SO1 1-12.1.6 n.d. n.d. n.d.

1-12.1.7 268 0.71 X012 SO1 N
1-12.1.8 N 211/213 0.55 X012 SO1 HN
Br For 1-12.1.1, 1-12.1.2, 1-12.1.3,1-12.1.5, 1-12.1.7 and 1-12.1.8 sodium hydride and DMF is used instead of potassium cabonate and ACN.
For I-12.1.3, I-12.1.7 and I-12.1.8 the reaction temperature is r.t.
For 1-12.1.4 DMF is used.
For I-12.1.6 the reaction conditions differ: 1,1-Difluoro-2-trifluoromethanesulfonyl-ethane is used as alkylation reagent in triethylamin as solvent at r.t.
Step 2: Synthesis of Intermediate 1-12.2 1-12.1 (15.0 g, 63 mmol) and hydrazine hydrate (30 mL, 618 mmol) are heated to 125 C for 72 h.
To the cool reaction mixture DCM is added and extracted with water and 1 M
HC1. The organic layer is dried over MgSO4 and concentrated. The crystallized residue is dissolved in DCM, methanol is added and the DCM is removed in vacuo. The crystallized product is filtered by sunction and washed with cold methanol. Yield 63%, m/z 226/228 [M+H]+, rt 1.16 min, LC-MS
Method V001_003.
The following intermediates as shown in Table 48 are synthesized in a similar fashion from the appropriate intermediates:
Table 48 Intermediate Structure m/z rt LC-MS method [M+H]+ (min) 1-12.2.1 ¨N/ n.d. n.d. n.d.
Br, =0 1-12.2.2 283/285 0.832 n.d.
IJ
7 \-0 1-12.2.3 Br 11.d. n.d. n.d.
Step 3: Synthesis of Intermediate R7 To 1-12.2 (32.0 g, 142 mmol) in anhydrous dioxane (400 nit) is added R3 (54.4 g, 241 mmol) and potassium acetate (41.6 g, 424 mmol). The mixture is purged with Argon, [1, F-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complex with dichloromethane (11.2 g, 14 mmol) is added and the mixture is heated to 90 C for 2 h. The reaction mixture is diluted with ethyl acetate and water, the organic layer is washed with water, dried over MgSO4 and concentrated. The residue is purified via flash chromatography (cyclohexanc /
EA = 70:30). Yield 72%, m/z 274 [M+H]+, rt 0.67 mm, LC-MS Method VO1 1_S01.
The following intermediates as shown in Table 49 are synthesized in a similar fashion from the 1() appropriate intermediates:
Table 49 rt Intermediate Structure nilz [M+H]+ LC-MS method (min) R7.1 0 325 [M+NH4]+ 0.30 X018_SO1 N

R7.2 ¨13 N 276 [M+H]+ 0.94 X002_002 > 0 ___721N1 0 40 R7.3 n.d. n.d. n.d.
SO2Me R7.4 318 0.92 Z018 SO4 R7.5 0 302 n.d. n.d.

R7.6 0 ri\I
294 0.85 Z018_SO4 \--00 0¨B
R7.7 260 0.65 X001004 0¨B
R7.8 n.d. n.d. n.d.

I I
N ¨S
H I I

R7.9 B 0 280 0.63 X001002 N

Synthesis of boronic ester R7.6:
2 g (10.3 mmol) 4-(4,4,5,5-Tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole and 2.9 mL (20.6 mmol) 4-(iodomethyl)-tetrahydro-2H-pyran are dissolved in 200 mL DMF and 4.274 g (30.9 mmol) K2CO3 are added. The mixture is shaken at 80 C for 5 h. After cooling to r.t. the mixture is filtered, the filtrate is concentrated in vacuo to approximately 60 mL. The product is separated using HPLC-MS (Gilson, mass flow 120 mL/min, 10 lam, 200g Sunfire RP18, ACN/water/TFA).
The product fractions are combined and freeze-dried to yield 115 mg product (3.8 %) R7.6.
Synthesis of boronic ester R7.8 to .. 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)aniline (1g, 4.56 mmol) and pyridine (10mL) are cooled down with an ice bath. Methanesulfonyl chloride (0.933 mL, 12.01 mmol) is dissolved in dichlormethane (10 mL) and added slowly dropwise. The reaction mixture is allowed to come to room temperature and concentrated. The residue is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is used without further purification.Yield: > 95%
Synthesis of boronic ester R7.9 Under nitrogen atmosphere to sodiumhydride (50%) (0.218 g, 4.54 mmol) and DMF
(3 mL) is added 4-(4,4,5,5-Tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (0.5 g, 2.5 mmol) and stirred for 30 min at rt.. N-(2-chloroethyl)acetamide (0.775 mL, 7.52 mmol) is added and stirred at 90 C
overnight. Due to no reaction N-(2-chloroethyl)acetamide (0.26 mL) and copper(I)iodide (25 mg, 0.13 mmol) arc added and stirred at 90 C for 24h. The reaction mixture is diluted with methanol, filtered through a thiol catridge and concentrated. The crude product is used without further purification.Yield: 100%
All other boronic acid derivatives R9 and R16 and alkynes R10 are purchased or prepared by literature known procedures.
Synthesis of tert-butyl (1S,25,4R)-2-(1-methoxycarbonylyinylcarbamoy1)-3-.. azab1cyc1012.2.1iheptane-3-carboxylate (R41) e0H
Nhipi H No R44 ,.0E1 I
C).<

1-22.1 R41 Step 1: Synthesis of Intermediate 1-22.1 To R5 (500 mg, 2.07 mmol) in DMF (5 mL) are added HATU (866.72 mg, 2.28 mmol) and DIPEA
(1.43 mL, 8.29 mmol) and stirred at r.t. for 15 min. To the reaction mixture is added methyl 2-amino-3-hydroxy-propanoate hydrochloride (354.64 mg, 2.28 rnmol) and stirred at r.t. for 4h. The reaction mixture is diluted with ACN and water and purified by reversed phase HPLC.
Yield 79%, m/z 343 [M+H]+, rt 0.44 min, LC-MS Method X011_S03.
Step 2: Synthesis of R41 1-22.1 (100 mg, 0.29 mmol) is dissolved in dichlormethane (2 mL) and cooled down to 0 C. 4-dimethylamino pyridine (1.78 mg, 0.015 mmol), TEA (65.13 ttL, 0.47 mmol) and methansulfonyl chloride (29.59 ttL, 0.38 mmol) are added and stirred at r.t. for 3h. The reaction mixture is diluted is with sodium carbonate solution. The organic layer is separated, dried and concentrated. The crude residue is purified by reversed phase HPLC.
Yield 27%, m/z 324 [M+H]+, rt 0.63 min, LC-MS Method X011_S03.
Synthesis of methyl (E)-2-(benzyloxycarbonylamino)-344-(1,4-dimethy1-4-piperidy1)-2-fluoro-phenyl]prop-2-enoate (R42) OH OH
\

______________________ 3 -3.
F ,OH R95 1-23.1 1-23.2 =0 0 N 1-23.3 0-Jy Step 1: Synthesis of Intermediate I-23.1 To 1-fluoro-2-methoxy-benzene (25 mL, 222.79 mmol) and 1,4-dimethylpiperidin-4-ol (7g, 54.18 mmol) is added trifluoromethanesulfonic acid (50 mL, 565.04 mmol) under ice bath cooling.
The reaction mixture is stirred at r.t. overnight, poured into iced water and extracted with PE.
To the aqueous phase is added solid sodium carbonate and extracted with ethyl acetate. The organic layer is dried and concentrated. The crude product is triturated with diisopropylether and the precipitate is filtered off. Yield 82%, m/z 238 [M+H]+, rt 0.39 min, LC-MS
Method X018_S02.
Step 2: Synthesis of Intermediate 1-23.2 To 1-23.1 (16.9g, 43.63 mmol) in dichlormethane (150 mL) is added boron tribromide 1M in dichlormethane (44 mL, 44mmo1) and stirred at r.t. overnight. The reaction mixture is diluted with dichlormethane and 10% K2CO3-solution. The resulting precipitate is filtered off. The aq. layer is repeatedly extracted with dichlormethane, the precipitate formed upon standing at rt is filtered off and washed with dichlormethane. The dichloromethane phase is concentrated and purified by reversed HPLC and freeze dried. The isolated precipitates and the corresponding HPLC fractions are combined to yield the desired product.
Yield 18%, m/z 224 [M+H]+, rt 0.61 min, LC-MS Method VO1 1_S01.

Step 3: Synthesis of Intermediate 1-23.3 To 1-23.2 (1.4g, 6.27 mmol) in anhydrous dichlonnethane (40 mL) triethylamine (1.8 mL, 12.985 mmol) is added and cooled down to -20 C. Trifluoromethanesulfonic acid anhydride (1.1 mL, 6.538 mmol) is added dropwise and stirred at ¨ 10 C for 30 min. The reaction mixture is diluted with dichlormethane, washed with K2CO3-solution and brine. The organic layer is dried and concentrated. The crude product is used for the next step without further purification. Yield 98%, itilz 356 [M+H]+, rt 1.30 min, LC-MS Method V011_S01.
Step 4: Synthesis of R42 2-benzyloxycarbonylamino-acrylicacidmethylester (2.274g, 9.67 mmol), bis(dibenzylideneacetone) palladium (0) (295 mg, 0.32 mmol), (2-biphenyly0di-tert-butylphosphine (345mg, 1.156 mmol) and lithium chloride (710mg, 16.73 mmol) are purged with argon. 1-23.3 (2.29g, 6.44 mmol) .. dissolved in DMF (15 mL) and triethylamine are added and stirred at 80 C
overnight.
The reaction mixture is concentrated, then diluted with dichlormethane and washed with 5%
K2CO3-solution. The organic layer is dried and concentrated. The crude product is purified by reversed phase HPLC.
Yield 33%, m/z 441 [M+H]+, rt 1.23 min, LC-MS Method VO1 l_S01.
The following intermediate as shown in Table 50 is synthesized in an analogous manner from the appropriate intermediate R41 and R91:
Table 50 Intermediate Structure m/z rt (min) LC-MS method [M+H]
R42.1 558 0.47 X018 SO1 0'4-1-4-0--Y
F I
N'Th Synthesis of (25)-2-amino-3-(4-benzyloxy-2-fluoro-phenyl)propanamide hydrochloride (R47) _\rora,, R48 0 *

1-24.1 -õ0 y 0 0 *0 1-24.2 H2N H2 1-24.3 CIH

Step 1: Synthesis of Intermediate I-24.1 R22 (22.58 g, 75.97 mmol) in Me-THF (50 mL) is cooled down to ¨ 10 C, 1,1,3,3-tetramethylguanidine (9.55 mL, 75.97 mmol) is added and stirred for 30 min. 4-benzyloxy-2-fluoro-benzaldehyde (15.9g, 69.06 mmol) dissolved in 100 mL Me-THF is added dropwise and stiffed for 3h at -10 C to 0 C. The cooling is removed and the mixture warms up to room temperature.
The reaction mixture is diluted with 300 mL Me-THF and extracted with water.
The organic layer is treated with activated carbon, dried over MgSO4 and concentrated.
The crude product is recristallized with cyclohexane and filtered off Yield 97%, m/z 402 [M+H]+, rt 0.80 min, LC-MS Method X018_S01.
The following intermediate as shown in Table 50.1 is synthesized in an analogous manner from the appropriate intermediates:

Table 50.1 Intermediate Structure m/z rt LC-MS method [M+H]+ (min) 1-24.1.1 H0 374/376 0.77 X018 SO2 -rg 0 Br .. Step 2: Synthesis of Intermediate 1-24.2 1-24.1 (2.8 g, 6.98 mmol) and (+)-1,2-bis((2s,5s)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(1) trifluoromethanesulfonate (250 mg, 0.346 mmol) in methanol (60 mL) are stirred under hydrogen (50 psi) at r.t. for 2 h.
Then the mixture is filtered and the filtrate is concentrated. . Yield 100%, rn/z 404 [M+H]+, rt 1.40 min, LC-MS
io Method VOOl_SOL
The following intermediates as shown in Table 51 are synthesized in an analogous manner from the appropriate intermediates:
Table 51 Intermediate Structure m/z rt LC-MS method [M+H]+ (mm) 1-24.2.1 01,'r140, 443 1.24 V011 SO1 F
1-24.2.2 560 0.68 X011 S03 jo_ N[,.1 1-24.2.3 H 376 n.d. n.d.

Br F-A
Step 3: Synthesis of Intermediate 1-24.3 1-24.2 (2.95 g, 6.95 mmol) is dissolved in anhydrous methanol (15 mL). Calcium chloride (812 mg, 7.32 mmol) and ammonia in methanol 7N (15 mL, 10.5 mmol) is added and stirred at r.t. overnight.
The reaction mixture is diluted with water (45 inL) and the precipitate is filtered off and washed with water.
Yield 90%, m/z 389 [M+H]+, rt 0.65 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 52 is synthesized an analogous manner from the appropriate intermediates:
Table 52 Intermediate Structure rniz rt LC-MS method [M+H]+ (min) 1-24.3.1 428 1.05 V011 SO1 F
1-24.3.2 545 0.57 X011 SO3 N ,r0 FH) 1-24.3.3 1 1-1 361;363 0.64 X018 SO2 Y )r [\1 -NH, 0 - ,Br Intermediate 1-24.3.1 is purified by reversed phase HPLC.
Step 4: Synthesis of R47 To 1-24.3 (2.42 g, 6.23 mmol) in dichlormethane (20 mL) is added HC1 in dioxane 4mon (7.79 mL, 31.15mmol) and stirred at r.t. for 3h. The reaction mixture is diluted with TBME and the precipitate is filtered off and washed with TBME.
Yield 95%, m/z 289 [M+H]+, rt 0.50 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 52.1 is synthesized in an analogous manner from the appropriate intermediates:

Table 52.1 Intermediate Structure m/z rt LC-MS method [M+H]+ (min) R47.1 C) 261/263 0.31 X018 SO2 jt NH2 CIH Br Synthesis of (2S)-2-amino-3-[4-(1,4-dimethy1-4-piperidy1)-2-fluoro-phenyllpropanamide R49 bN
F
1-24.3.1 R49 1-24.3.1 (625 mg, 1.46 mmol) and Pd/C 10% (150 mg) in methanol (60 mL) is stirred under hydrogen (50psi) at r.t. for 3.5h. The reaction mixture is filtered and concentrated.
Yield 99%, m/z 294 [M+H]+, rt 0.80 min, LC-MS Method VOII_SOL
Synthesis of (1-ethyl-3,6-dihydro-2H-pyridin-4-y1) trifluoromethanesulfonate (R51) 0 FFF s FF
6 N b 'N.N/ 18 The reaction is carried out under argon atmosphere.
Diisopropylamine (5.289 mL, 38 mmol) in anhydrous THF (25 mL) is cooled down to - 50 C. N-butyllithium in hexane 2.5M (13.786 mL, 34.47 mmol) is added dropwise and stirred for 45 min, then the solution is allowed to warm up to 0 C and cooled down to -50 C again.
1-Ethyl-4-piperidone (4g, 31.45 mmol) dissolved in 30 mL THF is added dropwise and stirred for 30 min.
R18 (11.797g, 33.02 mmol) dissolved in 30 mL THF is added dropwise. The cooling is removed and the reaction mixture stirred for 2h.
The reaction mixture is diluted with 50 mL toluene. The organic layer is washed with IN sodium hydroxide, halfsaturated brine, dried and concentrated. The residue is purified over silica gel.
Yield 15%, m/z 260 [M+H]+, rt 0.30 min, LC-MS Method X012_S01.
The following intermediates as shown in Table 53 are synthesized in an analogous manner from the appropriate intermediates:
Table 53 Intermediate Structure miz rt LC-MS method [M+H]+ (min) R51.1 o -0 'S' F 274 n.d. n.d.
irk<

R51.2 FF n.d. n.d. n.d.
o=osl=o R51.3 F o n.d. n.d. n.d.
F

R51.4 F F 322 1.41 VOi -S01 0=S=0 R51.5 F F 316 1.23 Z012 SO4 -S. 0 \N-4 R51.6 308 1.38 Vll_SO1 o, -o F
For Intermediate R51.2, R51.3, R51.4 and R51.6 the reaction conditions differ:
lithium bis(trimethylsilyl)amide is used and the reaction is carried out at -78 C. The crude product is used for the next step without further purification.
Intermediate R51.4 is purified over silica gel.
For Intermediate R51.5 the reaction conditions differ: lithium bis(trimethylsilyl)amide is used and the reaction is carried out at -50 C. The crude product is is purified over silica gel.
Synthesis of (5-ethyl-1-isobutyl-pyrazol-3-y1) trifluoromethanesulfonate (R54) OH
1-25.1 41 0 0R95 \ iN

( F-7( F F

Step 1: Synthesis of Intermediate I-25.1 Ethyl pent-2-ynoate (300 !..EL, 2 mmol), isobutylhydrazine hydrate (240 L, 2 mmol), methanol (1mL) and water (1mL) are stirred together in the microwave at 140 C for 15 min.

The crude product is used for the next step without further purification.
Step 2: Synthesis R54 Intermediate 1-25.1 (380 mg, 2 mmol) is dissolved in anhydrous dichlormethane (10 mL), DIPEA
(1.2 mL, 6.94 mmol) is added and cooled down to 0 C. Trifluoromethylsulfonyl trifluoromethanesulfonatc (375 !AL, 2.26 mmol) dissolved in dichlormethane is added dropwise and stirred for 45 min.
Another trifluoromethylsulfonyl trifluoromethanesulfonate (188 L, 1.13 mmol) is added and stirred for 30min. The reaction mixture is extracted with NaHCarsolution (5%).
The organic layer is separated, dried and concentrated. The residue is purified over silica gel.
Yield 21%, itz/z 301 [M+H]+, rt 0.86 min, LC-MS Method X018_S02.
Synthesis of 1-bromo-3-methylsulfony1-5-(2,2,2-trifluoroethoxy)benzene(R57) Br OH Br OH FF Br R55 1-26.1 Step 1: Synthesis of Intermediate 1--26.1 3 -bromo-5-methylsulfanyl-phenol (5g, 22.82 mmol) is dissolved in dichlormethane (100 mL) and cooled down to 0 C. 3-chloroperbenzoic acid (10.23g, 45.64 mmol) is added and stirred at r.t.
overnight. The reaction mixture is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is purified by reversed phase HPLC and freeze dried.
Yield 55%, m/z 251/253 [M+H]+, rt 0.47 min, LC-MS Method X018 _S01.
Step 2: Synthesis R57 To 1-26.1 (150mg, 0.597 mmol) and potassium carbonate (206.41 mg, 1.49 mmol) in DMF is added 1,1,1-trifluoro-2-iodo-ethane (147.196 L, 1.493 mmol) and stirred over 3 days at 85 C.

The reaction mixture is diluted with water, the precipitate is filtered off, washed with water and dried. Yield 52%, m/z 350/352 [M+H]+, rt 1.16 min, LC-MS Method V01 l_S01.
The following intermediates as shown in Table 54 are synthesized in a similar fashion from the appropriate intermediates:
Table 54 1ntermedi Structure nilz rt (min) LC-MS elab ate [M+H]+ method R57.1 F 332/334 1.01 V011 SO1 LG1SLA004 Br [M+NH4]+ 59 ov, -o R57.2 Br 296/298 1.11 VO1 1 SO1 LG1SLA004 [M+NH4]+ 95 `c) The two intermediates in the table above are purified by reversed phase HPLC.
Synthesis of 4-bromo-N1-methyl-benzene-1,2-diamine (R58) H2N Br H211 Br Br 0- _____________________________ N
_ HN
0¨ N
\\ R103 0 0 1-36.1 R58 Step 1: Synthesis of intermediate 1-36.1 To 4-bromo-2-nitro-aniline (10 g, 46.08 mmol) in DMF (200 mL) are added potassium carbonate (15 g, 108.53 mmol) and portionwise methylamine hydrochloride (3.11 g, 46.08 mmol) and stirred overnight at r.t...The reaction mixture is filtered and concentrated. The crude product is triturated with DIPE, filtered off and dried. Yield 86%
Step 2: Synthesis of R58 To 1-36.1(5.27 g, 22.81 mmol) in ethyl acetate is added platinum on carbon (550 mg) and stirred under hydrogen (5 bar) at r.t. for 4h. The reaction mixture is filtered through a pad of celite and concentrated. The crude product is used without further purification for the next step Yield 96%
Synthesis of 5-bromo-N,1-dimethyl-benzimidazol-2-amine (R60) N--"="\
I N
N
H2N Br < Br Br Br HN

1-27.1 1-27.2 Br N
H

Step 1: Synthesis of Intermediate I-27.1 4-bromo-1-n-methylbenzene-1,2-diamine (4.42g, 21.98 mmol), N,N-carbonyl-di-(1,2,3-triazole (4.178g, 24.18 mmol), and TEA (9.184 mL, 65.95 mmol) in THE (70mL) are stirred at r.t. for 30min, then heated under reflux overnight. The reaction mixture is concentrated, triturated with water, filtered off and dried. The residue is triturated again with DIPE and filtered off Yield 88%
Step 2: Synthesis of Intermediate 1-27.2 1-27.1 (4.41g, 19.42 mmol) and phosphoroxybromide (27.84g, 97.11 mmol) are stirred at 100 C for 3h. The reaction mixture is diluted with iced water. The precipitate is filtered off and triturated with DIPE.
Yield 89%
Step 3: Synthesis of R60 1-27.2 (200 mg, 0.69 mmol) and methylamine in methanol 2mol/L (2mL, 4 mmol) are stirred at 80 C for 16h. The reaction mixture is purified by reversed phase HPLC.
Yield 63%, nilz 240/242 [M+Fl]+,11 0.48 min, LC-MS Method X011_S03.
Synthesis of (7R,8aR)-7-methoxy-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-alpyrazine (R63) X o 0 N'-0 II ?

a CIH
_________________________ p R61 0¨ 0-1-28.1 1-28.2 HN
\
\

1-28.3 Step 1: Synthesis of Intermediate 1-28.1 To 2-(tert-butoxycarbonylamino)acetic acid (1.5g, 8.56 mmol) and HATU (3.58 g, 9.42 mmol) in DMF (15 mL) is added DIPEA (5.89 mL, 34.25 mmol) and stirred for 15min. Methyl (2R,4R)-4-methoxypyrrolidine-2-carboxylate hydrochloride (1.675g, 8.56 mmol) is added and stirred at r.t.
overnight. The reaction mixture is diluted with dichlormethan and NaHCO3-solution. The organic layer is separated and washed with brine, dried and concentrated. The crude residue is purified by reversed phase HPLC.
Yield 74%, m/z 317 [M+H]+, rt 0.47 min, LC-MS Method X018 S01.
Step 2: Synthesis of Intermediate 1-28.2 1-28.1 (2g, 6.32 mmol), hydrochloric acid in dioxane 4mol/L (10mL, 40 mmol) and dioxane (30mL) are stirred at r.t. overnight. The reaction mixture is directly used for the next step.
Step 3: Synthesis of Intermediate 1-28.3 To the reaction mixture from the previous step is added TEA till a pH value of 8 is reached. The precipitate is filtered off and the mother liquor is concentrated to isolate the desired product.
Yield 97%, m/z 185 [M+H]+, rt 0.18 min, LC-MS Method VO 1 1_S01.
Step 4: Synthesis of R63 To lithiumaluminium hydride lmoLL in THF (12.215 mL, 12.215 mmol) in THF (8mL) is added a solution of 1-28.3 (900mg, 4.886 mmol) in THE (4mL) dropwise and stirred at r.t. for 1.5h. Under cooling the reaction mixture is poured into aq. sodium hydroxide (lmol/L) and diluted with THF
(30m1). The precipitate is filtered off and the mother liquor is concentrated.
The residue is diluted with methanol and stirred a few minutes at 50 C. The precipitate is filtered off and the mother liquor is concentrated to give the crude product which is purified over amino phase silica gel.
Yield 36%
Synthesis of 3,4,4a,5,6,7,8,8a-octahydro-2H-2,6-naphthyridin-1-one (R65) 5,6,7,8-tetrahydro-2H-2,6-naphthyridin-l-one hydrochloride (250mg, 1.339 mmol), platinum oxide (100mg) and glacial acetic acid (10mL) are stirred under hydrogen (5bar) at r.t. for 24h.
The reaction mixture is filtered off and concentrated. The crude product is purified over amino phase silica gel.
Yield 71%.
Synthesis of 4-bromo-2-isopropyl-1-methylsulfinyl-benzene (R67) Br S -1-isopropyl-2-methylsulfanyl-benzene (400mg, 2.41 mmol) is dissolved in dichlormethane (4 mL) and cooled down to 0 C. Bromine (123.21 iL, 2.41 mmol) is added and stirred at r.t. for 3 days.
The reaction mixture is concentrated and purified by reversed phase HPLC.
Yield 53%, m/z 261/263 [M+H]+, rt 1.06 min, LC-MS Method VO1 l_S01.
m Synthesis of (3-bromophenypimino-dimethyl-oxo-sulfane (R70) Br /
S
Br 0 N

1-Bromo-3-iodo-benzene (250 uL, 1.96 mmol), (methylsulfonimidoyl) methane (219.188 mg, 2.353 mmol) , cesium carbonate (894.466 mg, 2.745 mmol) and dioxane (12mL) are purged with argon. (5-diphenylphosphany1-9,9-dimethyl-xanthen-4-y1)-diphenyl-phosphane (85.098, 0.147 mmol) and tris(dibenzylideneacetone)dipalladium(0) (44.89 mg, 0.049 mmol) are added, purged again with argon and stirred at 105 C for 3h.
The reaction mixture is filtered through a pad of celite. The filtrate is concentrated and purified by reversed phase HPLC.
Yield 94%, m/z 249 [M+H]+, rt 0.74 min, LC-MS Method Z018_SO4.
The following intermediate as shown in Table 55 is synthesized in a similar fashion from the appropriate intermediates:
Table 55 Intermediate Structure miz [M+H]+ rt (min) LC-MS clab method R70.1 Br 318 0.83 Z018 SO4 CCCYUJO02 OJN
Synthesis of 2-(4-amino-3-bromo-pheny1)-N-methyl-acetamide (R71) OH
Br Br To 2-(4-amino-3-bromo-phenyl)acetic acid (5 g, 21.73 mmol) in methanol (50 mL) and 5 dichlormethane (100 mL) is added at -5 C trimethylsilyldiazomethane in diethylether 2mol/L
(31.51 mL, 63.03 mmol) dropwise over a period of 30 min. The reaction mixture is allowed to warm up to r.t. and concentrated. The crude product is used without further purification.
Yield 95%, m/z 244/246 [M+H]+, rt 0.48 min, LC-MS Method X011_S03.
Synthesis of 2-(4-amino-3-bromo-phenyl)-N-methyl-acetamide; 2,2,2-trifluoroacetic acid (R72) N
0 0 0 OH-"c-Br Br Br Br NHR71 >,0y.NH >OyNH

1-29.1 1-29.2 1-29.3 OH

Br F F

Step 1: Synthesis of Intermediate 1-29.1 4-amino-3-bromophenylacetic acid methyl ester (22g, 81.12 mmol), di-t-butyl-dicarbonate (20.13g, 92.22 mmol), 4-dimethylaminopyridine (991.02 mg, 8.11 mmol) and dichlormethane (300 mL) are stirred together at r.t. overnight. The reaction mixture is extracted with KHSO4¨solution (10%), NaHCO3-solution and brine. The organic layer is separated, dried and concentrated. The residue is purified over silica gel.
Yield 8%, m/z 344/346 [M+H]+, rt 1.34 min, LC-MS Method VO11_S01.
Step 2: Synthesis of Intermediate 1-29.2 To 1-29.1 (4 g, 11.62 mmol) in dioxane (50 mL) is added a solution of lithium hydroxide (400 mg, 13.95 mmol) in water (5mL) and stirred at r.t. overnight. The precipitate is filtered by sunction and dried.
Yield 91%, m/z 274/276 [M+H-isobutene]+, rt 0.29 min, LC-MS Method X011_S03.
Step 3: Synthesis of Intermediate 1-29.3 To 1-29.2 (150 mg, 0.45 mmol) in DMF (2 mL) is added TBTU (175.04 mg, 0.55 mmol) and after 7 min methylamine 2mo1/L inTHF (0.9 ml, 1.82 mmol) is added. The reaction mixture is stirred at r.t. overnight and purified by reversed phase HPLC.
Yield 35%, m/z n.d. [M+H]+, rt 0.55 min, LC-MS Method X011_S03.
Step 4: Synthesis of R72 To 1-29.3 (97 mg, 0.28 mmol) in dichlormethane (2mL) is added trifluoracetic acid (0.5 mL) and stirred at r.t. for lh. The reaction mixture is concentrated.
Yield 99%, nilz 243/245 [M+H]+,11 0.26 min, LC-MS Method X012_S01.
Synthesis of 4-amino-3-fluoro-5-iodo-benzamide (R74) R73 1-30.1 R74 Step 1: Synthesis of Intermediate I-30.1 2-fluoro-6-iodo-4-(methoxycarbonyl)aniline (30g, 0.1 mol), ethanol (300mL) and NaOH 20% (30 mL) are stirred together under reflux for 2h.. The reaction mixture is diluted with water and acidified with KHSO4¨solution (1 mol/L). The precipitate is filtered off and recristallized with ethanol.
Yield 86%
Step 2: Synthesis of R74 To 1-30.1 (26g, 0.092 mol) in DMF (200mL) is added 1,1'-carbonyldiimidazole (17.8g, 0.11 mol) and ammonium carbonate (48g, 0.5 mol) and stirred at 50 C for 30min. The reaction mixture is concentrated and the residue is diluted with water. The precipitate is filtered off and recristallized with ethanol.
Yield 83%
Synthesis of 4-amino-3-fluoro-5-iodo-benzonitrile (R74.1) KlI

F or F
NA-1\1+
8 !IP

R74.1 To R74 (2 g, 7.14 mmol) in dichlomethane (50 mL) is added R2 (3.4 g, 14.28 mmol) and stirred at r.t. overnight. The reaction mixture is extracted with water. The organic layer is separated, dried and concentrated. The crude residue is filtered through a pad of silica gel (eluent (ethyl acetate/cyclohexane 3:7).
Yield 53%, m/z 263 [M+H]+, rt 0.47 min, LC-MS Method X012 S01.
io Synthesis of 3-tetrahydrofuran-3-y1-3,8-diazabicyclo[3.2.1]octane (R77) Cr0 N
CIH

1-31.1 R77 Step 1: Synthesis of Intermediate 1-31.1 To tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride (300mg, 1.21 mmol) in THF (5 mL) is added tetrahydrofuran-3-one (114.21 mg, 1.33 mmol) and sodium triacetoxyborhydride (349.78 mg, 1.57 mmol) and stirred at r.t. for 0.5h.
Sodium acetate (148.40 mg, 1.81 mmol) is added and stirred at r.t. overnight.

The reaction mixture is diluted with aq. sodiumhydrogen carbonate solution and extracted with ethyl acetate. The organic layer is separated, dried and concentrated. The crude residue is purified by reversed phase HPLC.
Yield 61%, m/z 283 [M+H]+, rt 0.61 min, LC-MS Method VO1 I_SOI.
The following intermediates as shown in Table 56 arc synthesized in an analogous manner from the appropriate intermediates:
Table 56 Intermediate Structure m/z rt (min) LC-MS
[M+H]+ method 1-31.1.1 ry 213 n.d. n.d.
¨N
N-1-31.1.2 0 303 1.34 VI I_SO1 y¨ 0 For 1-31.1.1 sodium cyanoborhydride and methanol is used instead of sodium triacetoxyborhydride and THF.
Step 2: Synthesis of R77 I-31.1 (206 mg, 0.73 mmol) and hydrochloric acid in ether lmon (5mL) is stirred at r.t. for 3h.
The reaction mixture is concentrated, diluted in dichlormethan/ methanol 7/3 and filtered over amino phase silica gel.
Yield 99%, m/z 183 [M+H]+, rt 0.28 min, LC-MS Method VO1 1 _S01.

The following intermediates as shown in Table 56.1 are synthesized in an analogous manner from the appropriate intermediates:
Table 56.1 Intermediate Structure m/z rt (min) LC-MS
[M+H]+ method R77.1 H n.d. n.d. n.d.
I I I
R77.2 H 203 0.91 V11 SO1 For R77.1 p-toluenesulfonic acid monohydrate is used for the deprotection.
Synthesis of tert-butyl 4-(5-bromo-2-oxo-indolin-1-yl)piperidine-1-carboxylate (R79) 0 ¨4-- 0 N >o o o p Br R78 1-38.1 Step 1: Synthesis of intermediate 1-38.1 To 1,3-dihydro-1-(piperidin-4-y1)-(2H)-indo1-2-one (200 mg, 0.93 mmol) in dichlormethane (5 mL) are added TEA (0.129 mL, 0.93 mmol) and di-t-butyl-dicarbonate (201.82 mg, 0.93 mmol).

The reaction mixture is stirred for 10min, diluted with water and sodium hydrogencarbonate solution and extracted with dichlormethane. The organic layer is dried and concentrated.
Yield >95%, m/z 261 [M+H-tert.butyl]+, rt 1.055 min, LC-MS Method Z020_S01.
Step 2: Synthesis of R79 Tert-butyl 4-(2-oxoindolin-1-yl)piperidine-1-carboxylate (100 mg, 0.32 mmol) in ACN is cooled down to -10 C, N-bromosuccinimide (56.47 mg, 0.32 mmol) is added and stirred at -10 C for 2h.
The reaction mixture is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is ussed for the next step without further purification.
Yield 99%, m/z 395 [M+H]+, rt 1.126 min, LC-MS Method ZO2O_S01.
Synthesis of 2-amino-N-cyclopropy1-3-iodo-benzamide (R82) , , ANH NH2 n2N R81 Synthesis of R82 To 2-amino-3-iodo-benzoic acid (200 mg, 0.76 mmol) in DMF (1 mL) TBTU (244.15 mg, 0.76 mmol) and DIPEA (245.69 pL, 1.52 mmol) are added and stirred at r.t. for 7 min.
Cyclopropylamine (52.69 L, 0.76 mmol) is added and stirred at r.t. overnight.
The reaction mixture is diluted with water and the precipitate is filtered off and dried.
Yield 89%, m/z 303 [M+H]+, P0.49 min, LC-MS Method X012_S01.
Synthesis of 6-bromo-1-(1-methyl-4-piperidyl)indolin-2-one (R85) I I + Br >colrir, 0 0 + 0 Br Br N, R83 011 Br NH
1-32.1 1-32.2 0 o Br Br o o 1-32.3 1-32.4 R85 Step 1: Synthesis of Intermediate 1-32.1 To sodium hydride 60% (1.536 g, 38.4 mmol) in DMSO (30 mL) under nitrogen atmosphere is added di-tert.butylmalonate ( 8.61 mL, 38.4 mmol) dropwise. The reaction mixture is stirred at 100 C for lb, cooled down to 10 C and a solution of 2,5-dibromonitrobenzene (4.93 g, 17.55 mmol) in DMSO (25mL) is added dropwise. After the addition the reaction mixture is stirred at 100 C for lh again.
The reaction mixture is poured into ammoniumchloride solution and the pH is adjusted with sodium hydrogensulfate to pH 7. Water and a mixture of ethylycetateicyclohexane 1/1 is added.
The aq. layer is extracted with this mixture. The organic layer is separated, washed with brine, dried and concentrated. The crude product is used for the next step without further purification.
Yield 45%, m/z 414/416 [M+H]+, rt 1.215 min, LC-MS Method ZO1 l_S03.
is Step 2: Synthesis of Intermediate 1-32.2 To 1-32.1(1 g, 2.4 mmol) in ethanol is added platinum on carbon (50 mg) and stirred under hydrogen (50p5i) at r.t. for 67h. The reaction mixture is filtered and concentrated. The crude residue is purified by reversed phase HPLC.
Yield 34%, m/z 274/276 [M+H]+, rt 1.156 min, LC-MS Method ZO1 l_S03.

Step 3: Synthesis of Intermediate 1-32.3 To 1-32.2(316.66 mg, 0.81 mmol) in dichlonnethane (2 mL) and glacial acetic acid (73.88 mL, 1.22 mmol) are added Boc-4-piperidone (210.41mg, 1.06 mmol), titanium (IV)isopropoxide (346.17 mg, 1.22 mmol) and sodium triacetoxyborhydride (258.14 mg, 1.22 mmol) and stirred at 50 C for 3h and at r.t. over 3 days. The reaction mixture is diluted with dichlormethane and water. The organic layer is separated and concentrated. The crude product is purified by reversed phase HPLC.
Yield 27%, m/z 569/571 [M+H]+, rt 1.049 min, LC-MS Method Z011_1103.
m Step 4: Synthesis of Intermediate 1-32.4 To 1-32.3(125.3 mg, 0.2 mmol) in toluene (1mL) is added 4- ethyl-benzenesulfonic acid (163.9mg, 0.9 mmol) and stirred at 140 C by microwave irridation. The reaction mixture is concentrated and diluted with sodium hydroxide lmol/L and dichlormethane and concentrated again. The crude product is used without further purification for the next step.
Yield 92%, m/z 295/7 [M+H]+, rt 0.867 min, LC-MS Method ZO11_S03.
Step 5: Synthesis of R85 To 1-32.4 (60mg, 0.20 mmol) in methanol (1 mL) are added formaldehyde in water (37%) (75.67 pL, 1.02 mmol) and glacial acetic acid (17.44 pL, 0.31 mmol), stirred at r.t.
for 75min, afterwards sodium triacetoxyborhydride (107.70 mg, 0.51 mmol) is added. The reaction mixture is stirred at Lt. overnight.
The reaction mixture is diluted with sodium hydroxide lmol/L and dichlormethanc. The organic layer is separated, washed with brine, dried and concentrated. The crude product is used for the next step without further purification.
Yield 52%, m/z 309/311 [M+H]+, rt 0.912 min, LC-MS Method Z01 1_S03.
Synthesis of 6-bromo-N-methyl-111-benzimidazol-2-amine (R88) Br N H2 S=-=N Br R8 7 B r NH
N

1-33.1 Step 1: Synthesis of Intermediate 1-33.1 To 4-bromobenzene-1,2-diamine (0.5g, 3 mmol) in dichlormethane (10 mL) and DIPEA (0.55 mL, 3 mmol) is added methylimino(thioxo)methane (0.2 g, 3 mmol) and stirred at 50 C for 4h and at r.t. overnight. The reaction mixture is extracted with, aq. acetic acid (1%), aq. sodium carbonate (10%) and brine. The organic layer is separated, dried and concentrated. The residue is purified over silica gel.
Yield 69%, m/z 260/262 [M+H]+, rt 0.45 min, LC-MS Method X018_S02.
Step 2: Synthesis of R88 To 1-33.1 (130 mg, 0.50 mmol) in ACN (2.5 mL) are added benzotriazol-1-yl-oxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP reagent) (330 mg, 0.50 mmol) and DBU (150 ?IL, 1.00 mmol) and stirred at r.t. for 0.5h. The reaction mixture is purified by reversed phase HPLC.
Yield 51%
Synthesis of 4-(6-bromo-5-fluoro-tetralin-2-yl)morpholine (R9I) B
Br r To 6-bromo-5-fluoro-tetralin-2-one (1g, 4.11 mmol) and morpholine (0.36 mL, 4.11 mmol) in dichlormethane is added glacial acetic acid (0.52 mL, 9.05 mmol). The reaction mixture is cooled with an ice bath and sodium triacetoxyborhydride (1.74 g, 8.23 mmol) is added.
The reaction mixture is stirred at r.t. overnight. Morph line (0.2 mL) is added and stirred again at r.t. overnight.
The reaction mixture is basified with potassium carbonate solution (20%) and stirred for 15min.
The organic layer is separated and the aq. layer is washed two times with dichlormethane. The organic layers are dried and concentrated. The crude product is purified by reversed phase HPLC
Yield 57%, m/z 314/316 [M+H]+, P0.68 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 57 is synthesized in a similar fashion from the appropriate intermediates:

Table 57 Intermediate Structure m/z [M+H]+ rt (min) LC-MS
method R91.1 OH 172 n.d. n.d.
(N)0 Synthesis of 1-tetrahydrofuran-3-ylpiperidin-4-one (R91.2) (N)0 Cr0 R91.1 R91.2 To R91.1 1-tetrahydrofuran-3-ylpiperidin-4-ol (200 mg, 1.17 mmol) in dichlormethane (5mL) is added dess-martin periodine (595 mg, 1.40 mmol) and stirred at r.t. for 5h.
The reaction mixture is filtered through ALOX/N and washed with cyclohexane/ethyl acetate 1:3. The filtrate is concentrated.
m Yield 51%
Synthesis of (4a5,7aR)-2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazine (R93) = 0 = 0 ) 0 [7: C) \
HN
N
) N
N

" n H
1-34.1 Step 1: Synthesis of intermediate 1-34.1 To tert-butyl (4aS,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxylate (200 mg, 0.88 mmol) in methanol (3 mL) are added formaldehyde in water (37%) (26.44 mg, 0.33 mmol) and glacial acetic acid (79.71 mg, 1.31 mmol), stirred at r.t. for 75min, afterwards sodium triacetoxyborhydride (464.19 mg, 2.19 mmol) is added. The reaction mixture is stirred at r.t. for 2h Additional formaldehyde in water (37%) (26.44 mg, 0.33 mmol) is added and stirred in a 50 C
warm water bath for 10min, sodium triacetoxyborhydride (464.19 mg, 2.19 mmol) is added and stirred at r.t. for 1.5h.The reaction mixture is diluted with aq. sodium hydrogencarbonate solution and water and extracted with ethyl acetate. The organic layer is washed with aq. sodium to hydrogencarbonate solution and brine, dried and concentrated.Yield 79 The following intermediates as shown in Table 58 are synthesized in a similar fashion from the appropriate intermediates:
Table 58 Intermediate Structure m/z rt (min) LC-MS
[M+H]+ method 1-34.1.1 H n.d. n.d. n.d.
LJ
1-34.1.2 n.d. n.d. n.d.

H
Step 2: Synthesis of R93 To 1-34.1 (167 mg, 0.69 mmol) in dichlormethan (3mL) p-toluenesulfonic acid monohydrate (655.48 mg, 3.45 mmol) is added and stirred at r.t. overnight. The reaction mixture is extracted with sodium hydroxide lmol/L. The organic layer is separated dried and concentrated. Due to less yield the aq. layer is saturated with sodium chloride and extracted with dichlormahanc.
The aq layer is concentrated and extracted again with dichlormethane. All organic layers are combine, dried and concentrated. Yield 76%
The following intermediates as shown in Table 59 are synthesized in a similar fashion from the appropriate intermediates:

Table 59 Intermediate Structure m/z [M+H]+ rt (min) LC-MS
method R93.1 H n.d. n.d. n.d.
CNNH
R93.2 H n.d. n.d. n.d.
HN
'1s1 Synthesis of 1-bromo-4-(bromomethyl)-2,5-difluoro-benzene (R99) Br Br R98 Br R98 (31.4g, 15.17 mmol), N-bromosuccinimide (32.4 g, 1.6 mmol), AIBN (4.98 g, 30.34 mmol) in tetrachloromethane is heated at 90 C overnight. The reaction mixture is cooled down to r.t. and concentrated. The residue is dissolved in ethyl acetate and extracted with water. The organic layer m is dried over MgSO4, filtered and concentrated. The crude product is purified by high vacuum destillation (boiling point 95 C ¨ 98 C by oil bath temperature of 140 C) Yield 67%
The following intermediate as shown in Table 60 is synthesized in an analogous manner from the .. appropriate intermediates:
Table 60 Intermediate Structure m/z rt LC-MS method [M+H]+ (min) R99.1 Br 0 n.d. 0.65 X012 SO1 Br For R99.1 the reaction temperature is 80 C. For the work up the reaction mixture is cooled to r.t.
and the precipitate filtered off. The mother liquor is extracted with aq.
hydrochloric acid (lmol/L) and aq. sodium hydroxide (lmol/L), dried and concentrated. The crude product is used without further purification.
Synthesis of 2-benzyloxy-4-bromo-1-(chloromethyl)benzene (R100) Br OH
Br 0 Br 0 Br 0 R101 - 1-35.1 1-35.2 OH

m Step 1: Synthesis of intermediate 1-35.1 To methyl 4-bromo-2-hydroxy-benzoate (4.3 g, 18.61 mmol) in acetonitrile (50 mL) are added bromomethylbenzene (2.23 mL, 19.54 mmol) and potassium carbonate (3.86 g, 27.92 mmol) and stirred for 4h at reflux. The reaction mixture is cooled down to r.t., diluted with water and extracted with ethyl acetate. The organic layer is separated, dried over MgSO4 and concentrated. The crude residue is purified over silica gel (eluent: cyclohexane/ethyl acetate 95:5).
Yield 75%
Step 2: Synthesis of intermediate 1-35.2 1-35.1 (4.5 g, 14.01 mmol) is dissolved in THF (50 mL) and a solution of lithium aluminium hydride in THF (8.41 mL, 8.41 mmol) is added dropwise between 5 C -10 C. The reaction mixture is stirred lb under cooling and 1.5h at r.t.. Afterwards the mixture is cooled down and hydrolysed with 30mL aq. hydrodchloric acid (lmol/L), diluted with water and extracted with ethyl acetate.
The organic layer is washed with water, dried over MgSO4 and concentrated. The crude residue is used for the next step without further purification. Yield 94%
Step 3: Synthesis of R100 To 1-35.2 (3.85 g, 13.13 mmol) in dichlormethane (40 mL) is added triethylamine (2.21 mL, 15.76 mmol) and cooled down to 0 C - -2 C. Methanesulfonyl chloride (1.12 mL, 14.45 mmol) dissolved in dichlormethane (3mL) is added dropwise. The reaction mixture is stirred for lh at 2 C-5 C and overnight at r.t.. The reaction mixture is concentrated, diluted with dichlormethane and water. The organic layer is washed with lmol/L hydrochloric acid, water, dried over MgSO4 and concentrated.
The crude residue is used for the next step without further purification.
Yield 74%
Synthesis of tert-butyl N-(4-amino-3-bromo-phenyl)carbamate (R104) Br Br _-N
oo NH2 To tert-butyl N-(3-bromo-4-nitro-phenyl)carbamate (1 g, 3.15 mmol) in ethyl acetate (20 mL) is added tin (II) chloride dihydrate (3.56 g, 15.77 mmol) and stirred overnight at r.t..The reaction mixture is basified with potassium carbonate/ sodium hydroxide. The organic layer is separated, dried and concentrated. The crude product is used without further purification for the next step.
Yield 83%, m/z 287/289[M+H]+, rt 0.58 min, LC-MS Method X011_S03.
The following intermediate as shown in Table 61 is synthesized in an analogous manner from the appropriate intermediates:
Table 61 Intermediate Structure m/z rt LC-MS method [M+H]+ (min) R104.1 197/199 0.45 X012 SO1 N

Br Synthesis of 3,4,6,7,9,9a-hexahydro-1H-pyrido[2,1-c] [1,4]oxazin-8-one (R106) 0, _o o R108 0 0 o CIH 0 NO o:o 1-37.1 1-37.2 Step 1: Synthesis of intermediate 1-37.1 To methyl 2-morpholin-3-ylacetate hydrochloride (1 g, 5.11 mmol) in methanol (25 mL) are added TEA (0.785 mL, 5.63 mmol) and acrylic acid methyl ester (0.465 mL, 5.16 mmol) and stirred overnight at r.t.. Again acrylic acid methyl ester (0.465 mL, 5.16 mmol) is added and stirred 3 days at r.t..The reaction mixture is concentrated and the crude product is purified over silica gel (eluent:
io ethyl acetate).
Yield 93%, m/z 246[M+H]+, rt 0.77 min, LC-MS Method VO1 l_S01.
Step 2: Synthesis of intermediate 1-37.2 Under argon atmosphere 1-37.1 (1.09 g, 4.44 mmol) is dissolved in THF (40 mL) and cooled down to -70 C. Lithium bis(trimethylsily0amide lmol/L (9 mL, 9 mmol) is added dropwise and stirred for 4h at -70 C. The reaction mixture is quenched with hydrochloric acid lmol/L (15 mL).
Afterwards solid sodium carbonate (1 g) is added. The aq. layer is extracted with ethyl acetate. The organic layers are combined, dried and concentrated. The crude product is purified over silica gel (eluent: ethyl acetate). Yield 68%
Step 3: Synthesis of R1 06 1-37.2 (0.63 g, 2.96 mmol) and hydrochloric acid 4mo1/L (15 mL) are stirred at 100 C overnight.
The reaction mixture is diluted with water and freeze-dried. The crude product is filtered over amino phase silica gel (eluent: dichlormethane/methanol). Yield 82%
Synthesis of 5-bromo-2-methylsulfonyl-phenol (R109) I I
BrF HO Br OH

R110 R109 To 4-bromo-2-fluoro-l-methylsulfonyl-benzene (2 g, 7.9 mmol) in DMF (15 mL) is added 2-methanesulfonyl-ethanol (1.47 g, 11.85 mmol). Sodium hydride (948.16 mg, 23.71 mmol) is added in portions at 0 C . The reaction mixture is allowed to come to r.t. and is added dropwise into cooled aq.
hydrochloric acid. The aq. layer is extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and concentrated. The crude residue is purified by reversed phase HPLC.Yield 86%, m/z 251/253[M+H]+, rt 0.42 min, LC-MS Method X018_S01.
io EXAMPLES
(rt = retention time) Deprotection Methods: TSA (toluene sulfonic acid cf.
Example 1), SI
(trimethylsilyl iodide cf example 2 or 3), FA (formic acid cf. example 4 or 7), TFA (trifluoroacetic acid). Stereochemistry at the carbon atom adjacent to the nitrile group is assigned: Stereo bond means S-isomer, non-stereo bond means 1:1 mixture of stereoisomers.
Table 62 Syn. /
Yield Example Structure Educt Deprot.
[ /01 Method H N
1 1-1.5 A / TSA 47 N\
CH, N>.jYNIN
2 o 1-2.3 Al / SI 44 CH, o -_E
3 1-3.3 A2.1 / SI 62 H
NH
4 CH3 1-4.3 A3 / FA 86 , Sõ0 N / NH
0 ji 1-5.2 A4 / FA 34 H
N. F
6 1-6.2 A5 TSA 86 N-Th NH
N
7 1-7.3 B / FA 39 N-N

H)N
H
N
8 N o 1-8.2 C / SI 19 \ N
, N
H
H
N

9H 1-9.1 D / SI 32 HN
N
H

NIFNIN
H

/ 1-3.3.1 A2.1 1ST 25 N
F

H N
N

11 1-3.2.2 A2.1 1ST 17 F

H

et--12 F 1-2.3.1 Al/FA 36 o s-___.
II

fillIF\11...N

13 F Al/FA 56 2.3.7.1 N /

H
atrH ..õ,,N
N
H ;
o 14 o I-4.3.1 A3 / SI 43 F

S, .0 N
NN
H
H ,..--N
N =-=""
11.11( 15 o 1-4.3.2 A3 / ST 21 /
N
F

H

1-' NH H --.--.N Tr##1

16 1-4.3.3 A3 / TSA 93 ,o s-/ II
o H
o o N \

17 1-2.3.2 Al / TSA 16 F
H
N , S
0 kr _I

18 1-2.3.3 Al / TSA 36[\11 '''' F

N
N

19 I-4.3.1 A3 / SI 59 S, s 0 N N
11 'YIN

020 FTI1N\f -2.3.7.3 Al / TSA 22 21 Al / FA 49 2.3.7.4 EN.121 õirrH
N
22 1-4.3.5 A3 / SI 70 _N
0 j 23 1-2.3.4 Al / TSA 37 VI) H N
H I-24 0 Al TFA 45 2.3.74.1 cV H N
NH
25 1-4.3.6 A3 TSA 45 0 I 26 1-2.3.5 Al / TSA 49 0 I 27 1-2.3.6 Al / TSA 38 Y-"

28 Al/FA 75 2.3.7.5 1\ir 29 1-4.3.7 A3 / SI 40 N
30 1-2.3.8 Al TSA 46 VI) H ,...- N
o 31 1-4.3.8 A3 / SI 39 /
N

e, H .....-, N
E F

0 N 'Th 1-3.2.4 A2.2 / TSA 31 L.,__N
*

F F
F

\
V33 N 1-2.3.9 Al / TSA 16 I\
F

.j1 FIN
H
o 34 1-3.3.3 A2.1 / SI 32 o F

rilir, H N
N .---.
o 35 1-4.3.9 A3 / SI 77 F
F
H
N S
0 I \
\
36 k 1-2.3.10 Al / TSA 39 F

cc IN,),H, ,-N N
37 1-4.3.10 A3 / FA 98 F
H2N--..-õs, 0_ '0 H
N
A
\

NH N 1-2.3.11 Al / TSA 6 F
N _N
0 j \
N N--39 V: 1-2.3.12 Al / TSA 30 N ' F
-I

<TeH N
l L
40 1-2.3.13 Al / TSA 49 F S
I / ¨N

c c c : ,-N
N
41 1-4.3.11 A3 /FA >95 F

N
H
H

H N
NHF
42 1-3.2.6 A2.1 / TSA 75 N..

NH
F
43 1-3.2.7 A2.2 /

N-y-o L1\1) H N

44 Al/FA 64 2.3.7.6 N¨\
\-0 H N
Er\dNIpiN
45 1-4.3.12 A3 / SI 58 S¨C

N
46 1-2.3.14 Al / TSA

NH rdj =
N=N
47 ead A4 TSA 57 1\r-N
48 2.3.7.7 Al /FA 20 N¨( vi,,,L,H N N
/
49 1-4.3.13 A3 / FA 93 F
NH

H

H N
CGIF)1k N
50 \ 1-2.3.15 Al / TFA 31 1 ,N
N
d tc,,,,,,, N
N
51 1-4.3.14 A3 /FA 76 F
.0 S' -----N.r,"
H
1\111,,H ,A\J
N /
H F
o 52 o 1-4.3.4 A3 / SI 33 .0 N.
NN
H

vi_tH ,I\I
N
53 1-4.3.16 A3 / FA 85 F

LH N
N
NH
54 1-4.3.17 A3 / FA 96 ,0 /II

N/rErlN

55 Al /FA 71 NI 2.3.7.8 N
NH
56 1-4.3.18 A3 / FA 67 .0 S' 0 I /N 1-2.3.16 Al / TSA 38 VI:11 LH N
N
NH
58 1-7.3 B /FA 90 \
N-N

F
59 1-2.3.17 Al /FA 37 s N¨N

60 V 1-2.3.18 Al TSA 33 i\H
;1\1>IrrH
N
61 1-4.3.15 A3 / SI 47 N
NH
62 1-4.3.20 A3 /FA 91 NH
.S.
OTO
0 I .1\1 63 1-2.3.19 Al / TSA 19 N
64 V 1-2.3.20 Al / TSA 48 (' H

_N
N--65 1-2.3.21 Al / TSA 6 COTE:kil NN N
0 N'f)---Q---g 66 LNJ,, 1-5.2 A4 / TSA 23 ceH
N=N

67 "PI 1-5.2 A4 TSA 53 N
68 1-2.3.22 Al TSA 17 Vi\
N NH
69 1-2.3.23 Al TSA 19 H N
44(C?I'L E
70 1-2.3.24 Al / TSA 58 /N

V iH,N
N
71 1-4.3.21 A3 /FA >95 .0 s' II
\ 0 72 CH3 1-2.3.25 Al TSA 13 kr:H-Q\

it H N
73 1-2.3.26 Al TSA 53 .111(7>N1 2.3.7.9 Al TSA 41 H
75 1-3.3.4 A2.1 / SI 4 tõ, "H
N
76 1-4.3.22 A3 /FA 89 CH, 0-c I I N
77 I-5.2 A4 TSA 40 [CF
IN)ILN'''' (61 0 _N

1-2.3.27 Al TSA 7 N
NH
79 1-4.3.23 A3 /FA 80 NH

S-(CH, 0 kr80 %I N 1-2.3.28 Al TSA 24 CH, rj N
81 CI H3 1-4.3.24 A3 / SI 31 p I
=N / CH, I

CH, 1-5.2 A4 / TSA 44 NH ILN

N
N
NH
83 1-4.3.25 A3 / FA >95 NN

84 1-5.2 A4 / TSA 46 N., e, F N
85 II 1-2.3.29 Al /FA 60 -- s H
o eNH
F
86 1-2.3.30 Al /FA 63 o si?..
ii c1-13 o H
c"
H I I-o 87 Al / TSA 8 2.3.7.10 F--N-rCH, --- , -I

,,,H,,N

i,,,, . .CH, 1-4.3.26 A3 /FA 52 (D.
Sõ0 F

NF----N

J.0 89 HO'" CH 1-5.2 A4 / TSA 48 eN,, H
F
-I
N
N--=-N CH, I I ---i 0 o 90 1-5.2 A4 1 TSA 77 c,r,),, H
F

NH

411 1-3.2.9 A2.2 / TSA 92 N-Th o 92 [ 1-2.3.31 Al / TSA 14 CH, H N
<C11\)1E1 93 1-2.3.32 Al / TSA 54 sJK

H3C, N /
1-5.2 A4 / TSA 80 H
F
95 VNH 1-3.2.10 A2.1 / TSA 53 NH

NH
96 \ ;N 1-2.3.33 Al /FA 87 iN

H3q SO
97 o , N 1-2.3.34 Al TSA

/N
VE:k N
1-;1\->jClirH õ.N
98 1-3.2.11 A2.1 / SI 83 N

j.I /
99 \ .1-5.2 A4 / TSA 34 NH F
F F
I

0 ,N `i 1-2.3.35 Al / TSA 16 /\11 CH3 NN
CH, 101 HO 1-5.2 A4 / TSA 48 eHLN
HN
102 1-3.2.12 A2.1 / SI 29 NL

, 0 103 V 1-2.3.36 Al / TSA

104 1-2.3.37 Al TSA 8 N-'N\

105 CH, 1-5.2 26 TSA
NH F
N \

106 1-5.2 A4 TSA 30 NH F

TiNatH N
N
107 1-4.3.27 A3 /FA 80 N
N
108 1-3.2.13 A2.1 / SI 42 N, CI
109 HO CH, 1-5.2 A4 TSA 41 eh, ,\,N1 110 V 1-2.3.38 Al / TSA 21 IF 1\1 LOH, 0 N-ff---\0_CI-1, 111 =
1-5.2 A4 / TSA 84 eHNõ, NN
0 0¨\
112 \__(:) 1-5.2 A4 / TSA 22 NH F
H
113 1-2.3.39 Al / TSA 45 S CH, LHN
NH
114 1-2.3.40 Al TSA 53 N=NH
0 o 115 V\N OH 1-2.3.41 Al / TSA 30 i _N

N N

VI\N 1-2.3.42 Al / TSA 8 H I-117 2.3.43.1 Al / SI 57 N,CH3 N
V118 1-2.3.44 Al TSA 40 N...H*411 F F

0' 119 0 I I Ail N 1-5.2 A4 / TSA 37 NH F
Fr\le;i)j,TrH N
N
120 1-4.3.19 A3 / SI 5 HO

HC

z N
121 1-2.3.45 Al /TSA 41 N

122 1-4.3.19 A3 / SI 27 icH3 123 1-10.5 E / FA 10 HH

NN

-124 1-C? CH3El N CH3 1-5.2 A4 / TSA 36 F
1250 1-4.3.28 A3 TSA 79 N-N

126 1-2.3.46 Al / TSA 7 NH CH, H)N
127 N N I-8.2.1 C / SI 36 / N

128 HN 1\(1LrejN
1-10.5 E / FA 5 129 bH3 1-2.3.47 Al TSA 21 ...(CrjL\IH N

130 1-2.3.48 Al / TSA 33 <teLN

NH
131 1-2.3.49 Al TSA 28 ..steN
132 0 1-2.3.50 Al TSA 36 "
0 cH, 133 ji 1-2.3.51 Al TSA 28 NH
134 1-2.3.52 Al / TSA
<teLN
,N-C
135 1-2.3.53 Al TSA 25 <TeL.N

Q. N FL
S:o 1-2.3.54 Al / TSA 33 .4<trdHLN

1-2.3.55 Al TSA 25 ' N\

IN
1-2.3.56 Al TSA 41 <IteL'H
CH
N

139 1-2.3.57 Al TSA 26 4riCeLN
NH
140 1-2.3.58 Al / TSA 16 s-o 141 1-2.3.59 Al / TSA 28 4(1:(IeILH

N I
142 o 1-2.3.60 Al /TSA 24 H F

N
o õ
143 li 8 - '' 1-2.3.61 Al /TSA 33 , H F
H
N
o III
0 1-2.3.62 Al /TSA 34 144 H F
H
N,.... Ci 145 0 il 1-2.3.63 Al /TSA 21 H F
H
N
il o 146 o 1-2.3.64 Al /TSA 32 <11.NdE:ILH F
H
N

147 o 1-2.3.65 Al /TSA 34 NI
.õ, icitNeLN ' H F

NH

148 I I 1-2.3.66 Al TSA 10 <HF
.CH, I I 1-2.3.67 Al / TSA 23 iczel N "
HN.CH3 IC

150 01-2.3.68 Al /

151 1-2.3.69 Al TSA

.41ÃC1:

H N
1-eL.
152 1-2.3.70 Al /FA 68 0' '0 H
153 1-2.3.71 Al /FA 73 o=s=o H
F
154 1-3.2.14 A2.2 / TSA 59 is) 155 1-3.3.5 A2.1 / SI 62 ,p CI-1\1.

156 1-3.3.6 A2.1 / SI 25 H

157 Ih21-4.3.32 A3 /FA 36 \
S NF

158 0 ri 1-2.3.72 Al / SI 57 N
F

-I

e,ILH N
159 JZIILJ 1-1.5.1 A / TSA 65 F
S---() /II
N

N Ni 160 I'''' N 1-3.2.37 A2.1 / TSA 34 1:1=JICI
F
H

161 1-4.3.33 A3 /FA 75 1 \
S N-H

N
162 1-3.2.47 A2.1 /

F

N _N
0 I \
N N, 163 t 1-3.2.36 A2.1 /

F

H

164 1-4.3.34 A3 /FA 78 \
s N¨\

;
N 1\1>jr'EN11.
H

165 1-4.3.35 A3 / FA 90 1 \
so H
r_ji.rH
N'.

166 1-3.3.7 A2.1 / SI 33 F

NH
N
0 I 0 \
".=
167 1-3.2.46 A2.1 i TSA 49 VLF!
F
H
N
0 J _N
\
N N

L Fl 3 1-3.2.42 A2.1 i TSA 37 [-NFI:k N --F
H

,,,,,,_,,.õ õ
N. N
169 F 1-1.5.2 A/ TSA 79 NO
\

170 1-4.3.36 A3 /FA 77 F \ 0 I
S N-/

N _NJ

1-3.2.39 A2.1 / TSA 37 CrilH CH
F

V CH "' 1-3.2.38 A2.1 / TSA 36 F

N

173 N N 1-3.2.45 A2.1 / TSA 34 F
H
N N

\ 1-3.2.40 A2.1 / TSA 33 IFI CINI j '''' N ----F
H
N

1-3.2.50 A2.1 / TSA 44 F

IF\IT,H .- N
N

176 Al / FA 53 2.3.75.1 F

Nr-FNI
-,, 177 F 1-3.2.51 A2.1 / SI 59 ,p 0 _____________________________________________________________ e _AN

el 1-3.2.19 A2.2 / TSA 81 N
N,,,_.---..
H
N

179 N ''' s 1-3.2.49 A2.1 / TSA 35 VI
\
F

180 1-3.2.20 A2.2 / TSA 56 ,,,-N
!No Ei\_1:1Xl_r_H ,,N
N..,-I-181 0 2.3.76.1 Al !FA 31 H
N

F

H
e F

4111 1-3.2.22 A2.2 / TSA 31 NrTh 0 N,,) ii.c.rry _.N

183 I Al/FA 36 F 2.3.78.1 F
Oz---s, 'N
H

184 F 1-4.3.37 A3 / TFA 51 HNI.
I
-I
lizi,H _. N
1\1.

F
185 C 1-4.3.38 A3 /

N
N.N..

N

186 1-4.3.39 A3 / TFA 40 HN

N
187 1-3.2.24 A2.2 / ST 17 N

188 1-3.2.25 A2.2 / TSA 85 N
LN
N
189 1-3.2.26 A2.2 / TSA 13 n NH

F
190 1-3.2.27 A2.2 / TSA 19 191 Si N
1-3.2.28 A2.2 / TSA 84 H N
v,HL- F
192 1-3.2.29 A2.2 / TSA 75 =

N
193 140 1-3.2.30 A2.2 / TSA 42 0 I 194 1-3.2.41 A2.1 / TSA 33 0 _____________________________________________________________ ITNE.):LH
195 1-3.2.31 A2.2 / TSA 86 196 1-3.2.32 A2.2 / TSA 18 = N=
LN,N

H
F
197 1-3.2.33 A2.2 / TSA 68 = N`

198 0 j/
1-3.2.48 A2.1 / TSA 32 \

yEd`?
199 0 1-2.3.73 Al / SI 56 H N
N

200 1-4.3.40 A3 /TFA 51 N H

H N
N
201 0 2.3.43.2 A2 / SI 65 FTZf .1 N
H N
N

202 1-4.3.41 A3 TFA 52 //

HN
1-7.3.3 B / SI 56 N
F
204NH 1-3.2.34 A2.2 / TSA 90 NH
205 1-3.2.35 A2.2 / TSA 76 206 H I-9.1.1 D / SI 39 207 H I-10.4.1 E / TFA 28 208 [ 1-3.2.43 A2.1 TSA 22 CcH-H
209 1-7.3.4 B / SI 55 H

210 1-4.3.42 A3 TFA 46 1\1F11N
H

211 1-4.3.43 A3 / TFA 48 z/N
212 1-7.3.5 B / SI 54 H

H
N
z/N
213 1-7.3.6 B / SI 65 N-/..2....iF1 H

:.-='''. H _. N
N

214 I-1.5.3 A / TSA 72 F
'1\1 --%S.
0' '0 N

HN
215 H I-10.4.1 E / TFA 23 F

H N
N
0Ni 216 I-4.3.44 A3 /TFA 38 NF

217 I-3.2.52 A2.1 /ST .. 64 ,p 1`1\1"Th H N
N

\ N 2.3.77.1 Al/FA 24 <-0-3 i\rH N
H

I-219 F Al / SI 41 N 2.3.43.3 -.
-n H

1-8.2.2 C / SI 69 H
N

221 t / NiN)1\1 1-3.2.44 A2.1 / TSA 17 H \
F

,Ni,,,H
222 1-3.2.53 A2.1 /FA 59 --S- -.., 1-2.3.43 Al/SI 60 11>j%.1111.(-7"N
H E

224 1-2.3.79 Al/SI 47 o=s =0 (NI

NFINF
NH
225 0 1-4.3.45 A3/FA 15 \
S

H N
N
+NH -(N
226 1-4.3.46 A3/FA 53 A

1, NH
227 1-4.3.47 A3/FA 28 Ns' NH =
- --1-4.3.48 A3/FA 37 228 ' NSv A, NH
229 1-4.3.49 A3/FA 14 s2Thi H

230 1 1-4.3.50 A3/FA 47 F tO
"' S /N-\
\

H ,N
NH
231 J 1-4.3.51 A3/FA 30 'S

NH
232 1-4.3.52 A3/FA 60 F

H
NH
233 1-4.3.53 A3/FA 37 s ,NH

/ 0 1-4.3.54 A3/FA 71 ¨/
S

235 0 1-4.3.55 A3/FA 38 I \
S NH

H
236 e1-4.3.56 Al/FA 41 s H

1-4.3.57 Al/TSA 67 'N

H ,,N
NH N F
238 1-4.3.58 Al/FA 42 H 7,N
F
, 239 1-4.3.59 Al/FA 53 240 1-4.3.60 Al/FA 33 o N-N

H
F

241 1-4.3.61 Al/FA 41 I /
CN\

F
242 0 1-4.3.62 Al/FA 52 -243 0 Al/FA 62 2.3.7.11 F
N-S-K

H
- F
NH
244 1-4.3.63 Al/FA 43 r. 1 ii oN

245 1-4.3.64 Al/FA 42 0 rr T iN, -I
(>,........_ H

246 -, F 1 1-3.2.54 A2.1/SI

F

H ,,N
N.,.......õ.õ--17:IL F
247 1-3.2.92 A2.2/TSA 20 = N''.-- \
H

erIN.,..29 0 1-3.2.93 A2.2/TSA 78 1,õ,........-...,r,N H

C:YIT:lit' F

0 1-3.2.7 A2.2/TSA 6 N j rli....õ, 250 1-3.2.7 A2.2/TSA 7 0 -,,, N,..r----0 , 0 _____________________________________________________________ 251 1-3.2.55 A2.1/TSA 65 ,N
NH
252 1 1-3.2.56 A2.1/TSA 82 F

253 1-3.2.57 A2.1/TSA 73 N/
Ths1/ H

LHN
NH
254 1-3.2.58 A2.1/TSA 53 H
255 I 1-3.2.59 A2.1/TSA 58 NH
-t N
256 1-3.2.60 A2.1/TSA 52 N
if H N
CCIN1)-1 257 1-3.2.61 A2.1/TSA

N H

N
258 1-3.2.62 A2.1/TSA

, H N
N
"5" F
NHll 259 1-3.2.63 A2.1/FA 19 I I

H
N
F
NH
260 A2.1/FA 91 3.2.64.1 \

A.NH
261 3.2.64.2 A2.1/FA 79 No H ,N
C? N -F
NH
2.3.7.4.

1 Al /FA 53 o F
263 1-3.2.65 A2.1/FA 52 0'1 H N
VI-)-11L F
264 1-3.2.66 A2.1/FA 23 NN
I I

F
265 1-3.2.94 A2.2/TSA 14 140:1 N
.0 0 S' H,N,N
NH N E F 266 1-3.2.95 A2.2/TSA 8 S N''''=
05' , 0 / II

H

e. F
267 1-3.2.96 A2.2/TSA 41 . N ------N
__2 --( H

cr-k-0 1-3.2.97 A2.2/TSA 80 N
1,N

/
H

,,-,-,N
'. N F
NH , 269 1-3.2.98 A2.2/TSA 27 I
--"N-- `-r=-=\ /
N-7-'0 e,.....,..2.,:,...;;NF

0 1-3.2.99 A2.2/TSA 81 NM.'" \
L.õ,,N,/

o kil,.....õ, e, F I-271 A2.2/TSA 17 3.2.100 , 0 _____________________________________________________________ 3.2.101 A2.2/TSA 27 N
N
H
F
273 \ 1-3.2.67 A2.1/TSA 7 N¨N
(TY

F
NH I 1-3.2.68 A2.1/TSA 73 s H
N F
NH
275 1-3.2.69 A2.1/TSA 71 -o' H
LA NH N' F
=(\
276 [.1 1-3.2.70 A2.1/TSA 72 F F
o 277 o J 1-3.2.71 A2.1/TSA 2 -N
N-278 o 1-3.2.72 A2.1/TSA 13 F" `c) H N
N

279 1-3.2.73 A2.1/TSA 28 N¨

H
N

280 1-3.3.8 A2.1/SI 90 F
-N.
NH
281 1-3.3.9 A2.1/TSA 83 11,) 282 NH 1-3.3.10 A2.1/TSA 42 F
283 1-3.3.11 A2.1/TSA

NH t J1TIIII:1 ccIN-F-J;L- F
284 1-3.3.12 A2.1/TSA

H N
F
285 A2.2/TSA 81 ,N 3.2.117 No, FF

H N
F
286 A2.2/TSA 80 3.2.120 0 \

H
-7( F
õ NH E
287 A2.2/TSA 77 3.2.121 Q

o ,,,,,...L,H ,,,,,,N
L
288 1-4.3.65 A3/FA 68 ,-----\
0' \ /
H

, NH
289 1-4.3.66 A3/FA 66 0-----fK

-I
N =
H
290 o - 0 1-8.2.3 CiTSA 93 H
HN CD
1-18.2.3 F
N
291 I I 0 Dl/MSA 18 HN
,-Liel-\11,:i N
H

i N, N 1-18.2.1 il .., 292 r i H Dl/SI 11 HN ------- ,---- , '---- - , - N
H H

H
F- ----NI 1-18.2.2 ....- i T, F 0 H
293 Dl/SI 24 , N 1-18.2.4 294 o H Dl/SI 20 F H
N 1-18.2.5 295 F I 1 0 Dl/SI 13 HN N
N
H

H

F
, 1-18.2.6 N
296 F '''T ? H Dl/TSA 7 HN 7z-7^7^A\i%46\N

1 N 1-18.2.7 297 I Dl/SI 43 HH /..."..' N
,--------- 1-18.2.8 I N

----,----,-- ..---------- -------, 0 H Dl/SI 71 HN, ,..-----,õ, , , _,,- ,N----'=,,,Nõ
ji H
0 7..;

1-18.2.9 299 ----,.)--- ..r.,, , l'j o Dl/SI 55 Hri,,), Il o H
F I-N
I I o F 18.2.10 300 1 Dl/TSA 24 HN
N
H

F I-F' "r, 18.2.11 301 0 Dl/SI 27 I-IN 1 : It ..V1\11 0 H *...->
H
I-:1F,I\I
N 18.2.12 302 Dl/SI 58 H
I-N,:<,..
NI 0 H 18.2.13 303 Dl/TSA 29 o--.....--I
a I-N
304 11.
- H 18.2.14 Dl/SI 32 HN T i N,-[j H

H
CI
N
o H 1-18.2 305 Dl/MSA 14 -,, H

N
I-H
18.2.15 N
306 li 0 Dl/MSA 29 HN
),LreFN1 N
H

-I
N
I I
I -N 18.2.16 307 li 0 Dl/SI 36 F
HN
N
H

I I 0 18.2.17 308 Dl/SI 37 HN

0 18.2.18 309 Dl/MSA 11 HN, õ, o 310 I I 0 18.2.19 Dl/SI 63 HN

0 18.2.20 311 Dl/ST 13 18.2.21 312 0 Dl/SI 28 HNAN

0, .0 18.2.22 313 0 Dl/SI 7 HN

18.2.23 314 0 H Dl/MSA 25 HN N

N
315 , 1-21.3 Z/TSA 60 N
I-21.3.1 I

H
317 1-3.2.77 A2.1/TSA

N OH

H
CD:H.L'N

3.2.102 A2.2/TSA 83 H
" 0 F"-"0 1-19.1 W/S1 34 1\1"
H N
N

320 1-3.3.13 A2.1/SI 74 HN
321 o - 1-8.2.4 OTSA 91 N
F il H 18.2.24 Dl/TSA 30 HN

H 18.2.25 Dl/TSA 32 HN

FPpF II o 324 18.2.26 Dl/TSA 36 HN

325 F II 0 18.2.27 Dl/TSA 9 HN

F o H 18.2.28 Dl/TSA 30 o rli.,.....õAN

0 3.2.103 A2.2/TSA 62 N\-3____\__ NH
H

1:41...,......N

0 3.2.104 A2.2/TSA 86 Q,N \

3.2.105 A2.2/TSA 62 ION
1--)o o H....,.....õ..e eN E F 1-0 3.2.106 A2.2/TSA 59 NJ-1_1_ N
______________________________________________________________ 1 o eH F
Ni----A2.2/TSA 70 N 3.2.107 N
NCO

õ.1.4 rõ,(NH
332 1-3.2.79 A2.1/TSA 64 µp H N
F

3.2.108 A2.2/TSA 33 NH I
334 1-3.2.80 A2.1/TSA 11 _OH

H N
z F 1-3.2.109 A2.2/TSA 90 N'Th H N
F
336 A2.2/TSA 72 3.2.110 N'Th 0 _____________________________________________________________ eHL F
337 1-3.3.14 A2.1/TSA

H
338 1-3.3.15 A2.1/TSA

H N
339 1-3.2.83 A2.1/TSA

r10 krr 340 1-3.2.84 A2.1/TSA

ihN

HN

341 N 18.2.29 Dl/TSA 17 H N
F
342 1-3.2.85 A2.1/TSA 68 H
F
343 1-3.2.86 A2.1/TSA 35 F,T) H
344 1-20.1 Wl/TSA 28 LHN
345 3.2.111 A2.2/TSA 2 '1\1 /
1211-,H
F N
346 1-3.2.87 A2.1/TSA 14 N

H

Tkil...........,AN
T:J:1- F
347 1-3.2.88 A2.1/TSA 18 N /
N
H
N
H

e 348 F N 1-3.3.16 A2.1/TSA 76 N

cte-- i 349 1-3.3.17 A2.1/TSA 73 F N

0 _____________________________________________________________ e11.1 350 1-3.3.18 A2.1/TSA

H
NH

H
F
352 3.2.112 A2.2/TSA

KNH

411 1-3.3.19 A2.1/TSA

H ,>1\1 N
NH
1-3.3.20 A2.1/TSA 62 H
N

F

3.2.114 f--.......--0, A2.2/TSA 88 ' N

H

T F

r\IH
A2.2/TSA >95 I-3.2.115 , H
s, ',./.=,o H
N

..<5, H
NH
H
' = õ ir, N , N
F

H A2.2/TSA 80 3.2.116 iTi N

H

358 Ex 359 A2.1 35 N-..

H
359 A2.1/TSA 61 3.2.136 N -..
ANALYTICAL DATA OF EXAMPLES
Table 63 m/z m/z Ex. [M+ rt [min] LC-MS-Method Ex. [M+ rt [min] LC-MS-Method H]+ H]+
1 419 1.16 V011_501 23 410 0.78 004_CA01 2 433 0.59 ,X011_501 24 451 0.69 Z018 504 3 420 0.41 X016_501 25 385 0.64 Z018_504 4 442 0.65 Z018_504 26 382 0.68 004_CA01 470 0.70 Z018_504 27 368 0.82 004_CA01 6 386 0.98 V011 501 28 452 0.70 Z018_504 7 410 0.96 V018_501 29 419 0.41 Z001_002 8 310 0.86 V011_501 30 396 0.73 004_CA01 9 387 0.39 X012_501 31 451 1.12 VO1 1 SO1 447 0.42 X012_501 32 448 1.28 V011_501 11 420 0.41 X012_501 33 438 0.93 004 CA01 12 460 0.67 Z018_504 34 420 1.06 V011_501 13 426 0.63 Z018_504 35 407 1.10 V001007 14 467 0.86 V018_501 36 370 0.80 004_CA01 433 1.04 V001_007 37 443 0.62 Z018 504 16 442 0.65 Z018_504 38 439 0.60 004_CA01 17 428 0.81 004_CA01 39 382 0.64 004 CA01 18 370 0.80 004_CA01 40 407 0.72 Z018_504 19 467 0.86 V018_501 41 419 0.61 Z018 504 396 0.66 Z018_504 42 447 1.09 V011_501 21 438 0.64 Z018_504 43 428 0.95 VO1 1 501 22 419 0.41 Z001_002 44 412 0.63 Z018_504 m/z m/z Ex. [M+ rt [min] LC-MS-Method Ex. [M+ rt [min] LC-MS-Method HI+ KI-F
45 421 0.90 V012_S01 78 430 0.85 004_CA01 46 399 0.73 004_CA01 79 419 0.62 Z018_SO4 47 461 0.72 Z018_SO4 80 399 0.62 004_CA01 48 438 0.60 X018_S01 81 449 0.90 V012_S01 49 433 1.13 W018_SO1 82 441 0.63 Z018_SO4 50 438 0.66 Z018 SO4 83 407 1.09 W018 SO1 51 457 0.64 Z018_SO4 84 471 0.92 ZO11_SO3 52 n.d. n.d. n.d. 85 395 0.50 X018_SO1 53 407 0.61 Z018_SO4 86 460 0.67 Z018_SO4 54 442 0.63 Z018_SO4 87 426 0.66 Z018_SO4 55 493 0.64 Z018_SO4 88 442 0.64 Z018_SO4 56 443 0.60 Z018_SO4 89 427 0.75 ZO11_SO3 57 452 0.69 004_CA01 90 397 0.60 Z018_SO4 58 368 0.79 V018_SO1 91 450 0.98 VO11_SO1 59 456 0.43 X018_SO1 92 368 0.81 004_CA01 60 418 0.80 004_CA01 93 397 0.65 Z018_SO4 61 451 0.88 V018 SO! 94 461 0.90 ZOl1_S03 62 457 0.64 Z018_SO4 95 419 0.82 V012_SO1 63 382 0.64 004_CA01 96 431 0.78 Z018_SO4 64 410 0.78 004_CA01 97 412 0.65 004_CA01 65 382 0.64 004_CA05 98 400 0.94 V012_SO1 66 463 0.79 Z011_SO3 99 468 0.73 Z011_SO3 67 395 0.82 Z011 SO3 100 436 0.82 004 CA01 68 396 0.73 004_CA01 101 413 0.70 ZOl1_S03 69 354 0.54 004_CA01 102 400 0.92 V012_SO1 70 430 0.72 Z018_SO4 103 354 0.76 004_CA01 71 456 0.67 Z018_SO4 104 368 0.79 004_CA05 72 412 0.76 004_CA01 105 413 0.79 ZOl1_S03 73 354 0.70 Z018_SO4 106 482 0.81 ZOl1_S03 74 466 0.70 Z018_SO4 107 435 1.25 W018_S01 75 364 0.50 X012_SO1 108 400 0.82 V012_SO1 76 433 0.65 Z018_SO4 109 441 0.80 ZOl1_503 77 491 0.86 ZO1l_SO3 110 382 0.67 004_CA01 m/z m/z Ex. [M+ rt [min] LC-MS-Method Ex. [M+ rt [min] LC-MS-Method HI+ KI-F
111 399 0.58 Z018_SO4 144 454 0.73 004_CA01 112 443 0.75 ZOII_SO3 145 411 0.78 004_CA01 113 411 0.70 Z018_SO4 146 419 0.66 004_CA01 114 354 0.59 Z018_SO4 147 431 0.64 004_CA01 115 414 0.68 004_CA01 148 445 0.68 004_CA01 116 438 0.68 004 CA01 149 445 0.69 004 CA01 117 385 0.65 V012_SO1 150 469 0.73 004_CA01 118 436 0.77 004_CA01 151 468 0.76 004_CA01 119 461 0.93 ZO1l_SO3 152 460 0.67 Z018_SO4 120 431 0.81 V018_SO1 153 468 0.70 Z018_SO4 121 383 0.71 004_CA01 154 456 1.08 VO11_SO1 122 521 0.97 V018_SO1 155 526 0.80 V012_SO1 123 387 0.38 X012_SO1 156 448 0.47 X012_SO1 124 427 0.83 ZO1l_SO3 157 413 0.61 Z018_SO4 125 400 0.83 VOI l_SO1 158 477 0.87 V012_SO1 126 382 0.66 004_CA01 159 467 0.85 V018_SO1 127 310 0.92 _VOI I_SOI 160 382 0.64 004_CA05 128 387 0.35 X012_SO1 161 427 0.64 Z018_SO4 129 447 0.76 004_CA01 162 379 0.76 004_CA05 130 419 0.64 004_CA01 163 368 0.61 004_CA05 131 433 0.71 004_CA01 164 455 0.71 Z018_SO4 132 419 0.84 004_CA01 165 467 0.70 Z018_SO4 133 440 0.83 004 CA01 166 448 0.48 X12_SO1 134 431 0.67 004_CA01 167 397 0.56 004_CA05 135 430 0.74 004_CA01 168 405 0.66 004_CA05 136 455 0.67 004_CA01 169 469 1.02 VO11_SO1 137 430 0.78 004CA01 _ 170 441 0.67 Z018_ _ SO4 138 394 0.70 004CA01 171 430 0.83 004_ _ CA05 139 469 0.74 004CA01 172 415 0.87 004_CA05 140 469 0.73 004CA01 _ 173 411 0.78 004 CA05 141 454 0.72 004CA01 _ 174 405 0.63 004 CA05 142 402 0.73 004CA01 _ 175 412 0.74 004 CA05 143 455 0.68 004_CA01 m/z m/z Ex. [M+ rt [min] LC-MS-Method Ex. [M+ rt [min] LC-MS-Method HI+ HI+
176 460 0.67 Z18_SO4 200 491 0.67 Z018_SO4 177 511 1.05 V012_SO1 201 399 0.32 X012_S02 178 444 1.10 VOl1_SO1 202 477 0.66 Z018_SO4 179 442 0.86 004_CA05 203 359 0.46 X12_S01 180 354 0.36 X018_SO1 204 372 0.93 VO11_SO1 181 437 0.65 Z018_SO4 205 373 1.05 V011_S01 182 430 0.26 X018_SO1 206 401 0.43 X12_SO1 183 485 0.67 Z018_SO4 207 405 0.41 X12_SO1 184 435 0.67 Z018_SO4 208 382 0.60 004_CA05 185 490 0.55 Z018_SO4 209 372 0.52 X12_SO1 186 421 0.63 Z018_SO4 210 475 0.74 Z018_SO4 187 412 0.26 X018_SO1 211 435 0.67 Z018_SO4 188 400 1.10 VOl1_SO1 212 360 0.48 X12_SO1 189 416 0.88 VOl1_SO1 213 359 0.43 X12_S01 190 416 0.89 VOl1_SO1 214 467 1.02 V011_S01 191 458 1.14 VOl1_SO1 215 405 0.37 X12_SO1 192 400 1.10 VOl1_SO1 216 461 0.70 Z018_SO4 193 456 1.00 VOl1_SO1 217 513 0.92 V012_SO1 194 405 0.55 004_CA05 218 470 0.69 Z018_SO4 195 399 1.42 VOl1_SO1 219 461 0.82 V012_SO1 196 414 0.65 V018_SO1 220 320 0.39 001_CA07 197 371 1.28 VOl1_SO1 221 394 0.59 004_CA05 198 442 0.84 004_CA05 222 466 0.65 Z018_SO4 199 461 1.24 V012_SO1 Ex. in/z [M+11[-i- rt LC-MS-[min] Method 223 383 0.31 X012_502 224 526 0.36 X012_501 225 496 0.54 Z018_504 226 519 1.17 Z018_504 227 524 0.56 2018_504 rt LC-MS-Ex. m/z [M+11[+
[min] Method 228 540 0.83 Z011_S03 229 522 0.9 Z011_S03 230 483 0.8 Z011_S03 231 524 0.77 Z011_S03 232 564 1.31 Z018_SO4 233 510 0.76 Z011_S03 234 538 0.95 Z018_SO4 235 497 0.82 Z011_S03 236 413 0,60 Z018_SO4 237 519 0.68 Z018_SO4 238 522 0.66 Z018_SO4 239 397 0.37 Z018_SO4 240 503 0.64 Z018_SO4 241 480 0.53 Z018_SO4 242 425 0.64 Z018_SO4 243 494 0.74 Z018_SO4 244 407 0.73 Z018_SO4 245 490 0.56 Z018_SO4 246 547 1.05 V012_SO1 247 400 0.58 X011_S03 248 440 0.97 V011_SO1 249 428 0.97 V011_SO1 250 428 0.97 V011_SO1 251 468 1.14 V011_SO1 252 522 0.61 X011_S02 253 447 0.67 X011_S03 254 395 0.56 004_CA05 255 395 0.55 004_CA05 256 452 0.60 004_CA05 257 381 0.5 004 CA05 258 381 0.50 004_CA05 259 455 0.64 n.d.

LC-MS-Ex. m/z [M+11[+ rt [min] Method 260 438 0.66 Z018_SO4 261 438 0.65 Z018_SO4 262 438 0.65 Z018_SO4 263 466 0.65 Z018_804 264 525 1.19 Z018_SO4 265 461 0.59 003_CA04 266 459 0.6 003_CA04 267 428 0.61 004_CA07 268 427 0.59 004_CA07 269 442 0.78 003_CA04 270 412 0.82 003_CA04 271 426 0.65 n.d.
272 400 1.13 V011_SO1 273 438 0.73 X011_S03 274 426 0.47 002_CA07 275 486 0.56 002_CA07 276 540 0.58 002_CA07 277 504 0.57 Z020_SO1 278 490 0.54 n.d.
279 490 0.53 Z020_SO1 280 413 0.35 X012_S02 281 425 1.03 V011_SO1 282 425 1.02 V011_SO1 283 427 0.49 004_CA07 284 427 0.46 004_CA07 285 422 1.26 V011_SO1 286 425 0.58 004_CA05 287 467 0.57 004_CA05 288 467 0.64 Z018_SO4 289 480 0.53 Z018_SO4 290 394 1.28 V011_SO1 291 448 0.64 Z011_S03 170,90-500 SL '0 S017 ZZE

ZOS-ZIOX TE'0 1017 61E

170V3 E00 19'0 18E LIE
TOS-ZTOX 15'0 ILL 91E

TOS ZIOX 9Z '0 Z017 171E
- TOS ZTOX EE*0 5917 LIE
50V3-1700 Z9'0 LT17 ZIE
EOVD-Z00 Z5'0 51717 TIE
170VD-E00 EL'O EZ17 OIL
50V3-1700 090 ZTtr 605 LOVD-T00 SE'0 5017 80E
50)90-1700 950 0517 LOS

EOVD-Z00 I5=0 la' 1705 - _ ZOS ZTOX L17'0 9Z17 SUE
EOVD-Z00 E5'0 0817 ZOE

- -LOS ZTOX TVO EZtr 00E
EOVD-Z00 8170 51717 66?
- TOS ZIOX LEI) Zit 86?
LOVD-T00 6E'0 1Z17 L6Z
?OS ZTOX 6170 117$ 96?

LOVD-TOO 9E '0 50tr 176?

potpaN luau]
= 41 An+inil z/tu =xa SZE
176Lfg0/17110LIAL1d SLOOPI/t 10Z
OM

rt LC-MS-Ex. m/z [M+11[+
[min] Method 324 441 0.56 005_CA01 325 448 0.53 005_CA01 326 419 0.83 003_CA04 327 384 0.46 002_CA07 328 412 0.74 004_CA05 329 468 0.66 X011_S03 330 398 0.8 003 CA04 331 442 0.72 003_CA04 332 439 0.62 X011_S03 333 412 1.15 V011_SO1 334 502 0.54 Z020_SO1 335 372 0.93 V011_SO1 336 456 0.67 004_CA05 337 441 0.63 X011_S03 338 441 0.29 X018_S02 339 544 0.35 X012_SO1 340 540 0.83 003_CA04 341 470 0.40 X012_S01_ 342 452 0.47 004_CA07 343 445 0.48 004_CA07 344 414 0.74 004_CA05 345 428 0.30 X012_501 346 516 0.98 Z011_S03 347 433 0.96 V011_SO1 348 468 1.09 V011_SO1 349 412 1.14 V011_SO1 350 415 0.79 003_CA04 351 427 0.57 X011_S03 352 413 1.11 V011_SO1 353 412 0.78 004_CA05 354 468 0.81 003_CA04 355 428 0.90 2011_S03 Ex. m/z [M+H[+ rt LC-MS-[min] Method 356 442 0.91 Z011_S03 357 442 0.93 Z011_S03 358 425 0.71 Z012_804 359 423 1.06 Z011_S03 Examples representing mixtures of stereoisomers can be detected and resolved into single stereoisomers through analytical and preparative chiral chromatography.
Representatives of examples for this process are given in Table 64 Table 64 The abbreviation "Dist. example" refers to the distomer of the given example.
Example Analytical SFC Data Prep.
SEC
Stereoisomer rt Method Stereoisomer 1 rt 2 [min]
Methode (Exampl No.). [min] (Example No.) Dist.-2 5.67 chiral I_ASH_30_10MIN_SS4P.M 2 3.94 SFC E
22 I ADH 40 MEOH Dist.-29 5.76 chiral DEA M 29 3.60 _ .
SFC D
43 chiral I ADH 15 MEOH DEA M 249 _ . 7.43 250 8.72 SFC C
Table 65 io List of Abbreviations ACN acctonitrile AIBN 2,2'-azobis(isobutyronitrile) ALOX aluminium oxide aq. aqueous BOC tert. butyloxycyrbonyle-day DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichlormethane DEA diethylamine DIPEA n,n-diisopropylethylamine DIPE diisopropyl ether DMAP 4-dimethylaminopyridine DMF n,n-dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate FA formic acid hour HATU o-(7-azabenzotriazol-1-y1)-N,N,N1,N'-tetramethyluronium hexafluoro-phosphate LiOH lithium hydroxide Me0H methanol MSA methanesulfonic acid MeTHF methyl tetrahydrofuran NaH sodium hydride PE petrol ether RT, r.t. room temperature, e.g. 15 -25 C
rt retention time SI trimethylsily1 iodide TBME tert-butyl methyl ether TBTU o-(1H-benzo-1,2,3-triazol-1-y1)-N,N,N',N'-tetramethyluronium tetrafluoroborate TEA triethylamine TEA trifluoroacetic acid THF tetrahydrofuran TSA toluene sulfonic acid PHARMACOLOGICAL DATA
Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention.
INHIBITION OF HUMAN DPPI (CATHEPSIN C) to Materials: Microtiterplates (Optiplate-384 F) were purchased from PerkinElmer (Prod.No.
6007270). The substrate Gly-Arg-AMC was from Biotrend (Prod.-No.808756 Custom peptide).
Bovine serum albumin (BSA; Prod.No. A3059) and Dithiothreitol (DTT; Prod.No D0632) were from Sigma. TagZyme buffer was from Riedel-de-Haen (Prod.-No. 04269), NaCl was from Merck (Prod.-No. 1.06404.1000) and morpholinoethane sulfonic acid (MES), was from Serva (Prod.-No.
29834). The DPPI inhibitor Gly-Phe-DMK was purchased from MP Biomedicals (Prod.-No.03DK00625). The recombinant human DPPI was purchased from Prozymex.
All other materials were of highest grade commercially available.
The following buffers were used: MES buffer: 25 mM MES, 50 mM NaCl, 5 mM DTT, adjusted to zo pH 6.0, containing 0.1% BSA; TAGZyme Buffer: 20 inM NaH2PO4, 150 mM NaCl adjusted to pH
6.0 with HC1 Assay conditions: The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 ittg/ml, respectively), and then activated by mixing in a 1:2 ratio with a Cysteamine aqueous solution ( 2mM) and incubating for 5 mM at room temperature.
Five uL test compound (final concentration 0.1 nM to 100 M) in aqua bidest (containing 4%
DMSO, final DMSO concentration 1%) were mixed with 10 uL of DPPI in MES buffer (final concentration 0.0125 ng/uL) and incubated for 10 min. Then, 5 itL of substrate in MES buffer (final concentration 50 M) were added. The microtiter plates were then incubated at room temperature for 30 min. Then, the reaction was stopped by adding 10 tit of Gly-Phe-DMK in MES-buffer (final concentration 1 uM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
Each assay microtiter plate contained wells with vehicle controls (1% DMSO in bidest + 0.075%
BSA) as reference for non-inhibited enzyme activity (100% Ctl; high values) and wells with inhibitor (Gly-Phc-DMK, in bidest + 1% DMSO + 0.075%BSA, final concentration litM) as controls for background fluorescence (0% Ctl; low values).
The analysis of the data was performed by calculating the percentage of fluorescence in the presence of test compound in comparison to the fluorescence of the vehicle control after io subtracting the background fluorescence using the following formula:
(RFU(sample)-RFU(background))*100/(RFU(control)-RFU(background)) Data from these calculations were used to generate 1050 values for inhibition of DPPI, respectively.
Table 66 Inhibition Inhibition of DPPI of DPPI
Example Example [PM] [AM
1 0,0086 17 0.0026 2 0,0020 18 0.0027 3 0,0007 19 0.0028 4 0,0014 20 0.0031 5 0,0040 21 0.0031 6 0,0107 22 0.0033 7 0.0019 23 0.0037 8 0.6794 24 0.0037 9 0.0096 25 0.0039 10 0.0015 26 0.0040 11 0.0017 27 0.0040 12 0.0019 28 0.0041 13 0.0019 29 0.0042 14 0.0020 30 0.0042 15 0.0020 31 0.0043 16 0.0026 32 0.0045 Inhibition Inhibition of DPPI of DPPI
Example Example IttM] LAM]
33 0.0045 65 0.0094 34 0.0046 66 0.0094 35 0.0046 67 0.0096 36 0.0047 68 0.0097 37 0.0047 69 0.0099 38 0.0048 70 0.0102 39 0.0051 71 0.0108 40 0.0051 72 0.0108 41 0.0053 73 0.0112 42 0.0053 74 0.0114 43 0.0056 75 0.0114 44 0.0059 76 0.0117 45 0.0063 77 0.0119 46 0.0069 78 0.0120 47 0.0072 79 0.0120 48 0.0072 80 0.0124 49 0.0073 81 0.0131 50 0.0074 82 0.0131 51 0.0075 83 0.0133 52 0.0076 84 0.0137 53 0.0079 85 0.0140 54 0.0082 86 0.0141 55 0.0082 87 0.0142 56 0.0083 88 0.0152 57 0.0083 89 0.0156 58 0.0084 90 0.0160 59 0.0085 91 0.0170 60 0.0087 92 0.0177 61 0.0087 93 0.0183 62 0.0091 94 0.0187 63 0.0093 95 0.0192 64 0.0093 96 0.0198 Inhibition Inhibition of DPPI of DPPI
Example Example IttMI LAM]
97 0.0199 129 0.0827 98 0.0203 130 0.0435 99 0.0211 131 0.1387 100 0.0223 132 0.0189 101 0.0239 133 0.0161 102 0.0248 134 0.0178 103 0.0249 135 0.2857 104 0.0249 136 0.0102 105 0.0250 137 0.0597 106 0.0259 138 0.0145 107 0.0259 139 0.0117 108 0.0264 140 0.0215 109 0.0269 141 0.0366 110 0.0286 142 0.0631 111 0.0318 143 0.0067 112 0.0333 144 0.0263 113 0.0364 145 0.0538 114 0.0367 146 0.0305 115 0.0378 147 0.0062 116 0.0391 148 0.0304 117 0.0396 149 0.0387 118 0.0443 150 0.0386 119 0.0512 151 0.0369 120 0.0556 152 0.0021 121 0.1565 153 0.0038 122 0.1817 154 0.0135 123 0.1866 155 0.0008 124 0.1869 156 0.0006 125 0.2060 157 0.0009 126 0.2751 158 0.0015 127 0.8597 159 0.0016 128 2.3930 160 0.0017 Inhibition Inhibition of DPPI of DPPI
Example Example ip,M1 LAM]
161 0.0019 192 0.0113 162 0.002 193 0.0123 163 0.0021 194 0.0133 164 0.0023 195 0.0147 165 0.0027 196 0.0151 166 0.0033 197 0.0156 167 0.0034 198 0.0158 168 0.0037 199 0.016 169 0.0041 200 0.0165 170 0.0042 201 0.0201 171 0.005 202 0.0229 172 0.0052 203 0.0233 173 0.0055 204 0.0245 174 0.0056 205 0.0259 175 0.0063 206 0.0263 176 0.0066 207 0.0291 177 0.0074 208 0.0298 178 0.0074 209 0.0458 179 0.0075 210 0.0494 180 0.0077 211 0.0611 181 0.0086 212 0.2955 182 0.0088 213 0.619 183 0.0088 214 0.8148 184 0.0088 215 0.8819 185 0.009 216 186 0.0096 217 0.0037 187 0.0098 218 0.0189 188 0.0098 219 0.0374 189 0.0104 220 0.253 190 0.0109 221 0.0037 191 0.0112 222 0.0022 Inhibition Inhibition of DPPI of DPPI
Example Example ip,M1 LAM]
223 0.0059 254 0.0020 224 0.0012 255 0.0109 225 0.0008 256 0.0263 226 0.0009 257 0.0399 227 0.0010 258 0.0079 228 0.0016 259 0.0060 229 0.0017 260 0.0035 230 0.0018 261 0.0042 231 0.0022 262 0.0064 232 0.0022 263 0.0118 233 0.0022 264 0.0170 234 0.0038 265 0.0627 235 0.0047 266 0.0437 236 0.0016 267 0.0105 237 0.0046 268 0.0111 238 0.0143 269 0.0094 239 0.0034 270 0.0063 240 0.0061 271 0.0059 241 0.0068 272 0.0068 242 0.0109 273 0.0289 243 0.0048 274 0.0065 244 0.0037 275 0.0330 245 0.0059 276 0.0141 246 0.0059 277 0.0030 247 0.0084 278 0.0010 248 0.0180 279 0.0055 249 0.0063 280 0.0212 250 0.0042 281 0.0033 251 0.0115 282 0.0037 252 0.0038 283 0.0097 253 0.0110 284 0.0138 Inhibition Inhibition of DPPI of DPPI
Example Example ip,M1 LAM]
285 0.0093 316 0.0424 286 0.0389 317 0.0520 287 0.0397 318 0.2120 288 0.0023 319 0.0175 289 0.0025 320 0.0096 290 0.0206 321 0.0568 291 0.0059 322 0.0008 292 0.0009 323 0.0008 293 0.0013 324 0.0010 294 0.0016 325 0.0013 295 0.0021 326 0.0019 296 0.0029 327 0.0034 297 0.0032 328 0.0042 298 0.0032 329 0.0070 299 0.0032 330 0.0078 300 0.0038 331 0.0093 301 0.0045 332 0.0129 302 0.0047 333 0.0153 303 0.0050 334 0.0220 304 0.0060 335 0.0245 305 0.0069 336 0.0245 306 0.0070 337 0.0282 307 0.0072 338 0.0443 308 0.0083 339 0.0013 309 0.0091 340 0.0018 310 0.0094 341 0.0076 311 0.0099 342 0.0013 312 0.0110 343 0.0045 313 0.0136 344 0.0100 314 0.0140 345 0.0184 315 0.0135 346 0.0010 Inhibition Inhibition of DPPI of DPPI
Example Example IttM] LAM]
347 0.0085 355 0.0224 348 0.0176 356 0.0200 349 0.0206 357 0.0338 350 0.0386 358 0.0220 351 0.0828 359 0.0088 352 0.0173 W009074829; Example 56 0.0441 353 0.0065 354 0.0068 LYSATE PREPARATION AFTER INCUBATION WITH TEST COMPOUND
Materials:
Optiplate 384F were purchased from PerkinElmer (Prod. No. #6007270). 24we11 Nunclon cell culture plates (No. 142475) and 96we11 plates (No. 267245) were from Nunc.
Dimethylsulfoxid (DMSO) was from Sigma (Prod.No. D8418). Nonidet-P40 (NP40) was from USBiological (Prod.No. N3500) Substrate, specific for Neutrophil elastase, was from Bachem (Me0Suc-Ala-Ala-Pro-Val-AMC;
Prod.No. 1-1270).
Human neutrophil elastase was from Calbiochem (Prod.No. 324681) Buffers:
Tris-buffer (100mM Tris; 1M NaCL; pH 7.5) Tris-buffer + HSA 0.1%; Human Serum Albumin from Calbiochem (Cat#. 126658) Serine-protease buffer (20mM Tris; 100mM NaCL; pH 7.5) + 0.1%HSA
Serine protease lysis buffer: 20mM Tris-HCL; 100mM NaCl pH 7.5; + 0.2% Nonidet-P40;
PBS: phosphate buffered saline, without Ca and Mg, from Gibco Cell culture:
U937 from ECACC (Cat.No. 85011440) cultured in suspension at 37 C and 5% CO2.
Cell density: 0.2-1 Mio. Cells/ml.

Medium: RPMI1640 GlutaMAX (No. 61870) with 10% FCS from Gibco Cell seeding and treatment:
Compounds in 100% DMSO were diluted in Medium (-FCS) with 10%DMS0 and further diluted according to the experiment planned.

20 1 of the compound solution was tranferred in the respective wells of the 24 well plate and diluted with 2m1 cell suspension/well containing 1105 cells/ml (final concentration of DMSO =
0.1%). Compound dilution factor = 100 Compounds (up to 7 concentrations) were tested in triplicates with 3 wells for the DMSO 0.1%
1() control, incubatet for 48 hours without medium change at 37 C, 5% CO2 and 95% relative humidity.
Cell harvesting and cell lysate:
Transfer the cell suspension in 2,2m1Eppendorf cups. Separate cells from medium by centrifugation (400 X g; 5min ; RT); discard the supernatant. Resuspend in lml PBS;
centrifugation (400 X g; 5min ; RT); wash cells twice with PBS. Add 100 1 Serin lysis buffer (ice cold) to the cell pellet; resuspend the pellet and store on ice for 15minutes.
Remove debris by centrifugation at 15000 X g for 10min at 4 C. Transfer 80-100 1 lysate supernatant in 96we11 plate and store immediately at -80 C.
Neutrophil elastase activiy assay:
Frozen lysates were thawn at 37 C for 10 minutes and stored on ice. Protein content was determined with Bradford protein assay. Lysates were diluted to 0.2-0.5mg/m1 protein in serine protease buffer + HSA.
Standard: NE (100 g/m1 stocksolution in Tris-buffer; stored at -80 C) was diluted in Tris-buffer +
HSA to 750 ng/ml, and further serially diluted 1:2 for the standard curve.
Buffer, blank, standard and lysate samples were transferred into 384 well plate Pipetting plan Blank: 5 1Tris-buffer + 10111 Tris-buffer+HSA + 5 1 Substrate Standard: 51.(1 Tris-buffer + 1010 NE (diff.conc.) + 51i1 Substrate Lysate: 5111 Tris-buffer + 10111 Lysat + 5 .1 Substrate The increase in fluorescence (Ex360nmlEm 460nm) is determined over 30 minutes with a Molecular Device Spectramax M5 Fluorescence Reader. Kinetic Reduction (Vmax units/sec); 4 vmax points. The amount of neutrophil elastase (ng/ml) is calculated using the standard curve and the Spectramax software. The result is interpolated to ng/mg lysate protein using excel formula functions. Percent inhibition in the compound-treated lysate samples is calculated relative to the DMSO-treated control-sample (100-(c ompound-s ample*100)/control-s ample) A test compound will give values between 0% and 100% inhibition of neutrophil elastase. 1050 is calculated using Graphpad Prism; nonlinear fitting (log(inhibitor) vs.
response -- Variable slope).
The 1050 value is interpolated as the concentration of test compound which leads to a neutrophil elastase activity reduction of 50% (relative to the DMSO-treated control).
Table 67 Reduction of NE-Example activity in U937 cells IC50 [ M]
1 0.0023 2 0.0062 3 0.0029 4 0.0064 6 0.0024 11 0.0087 16 0.0145 29 0.0088 42 0.0083 43 0.0092 154 0.0046 155 0.0005 156 0.0023 158 0.0088 169 0.0091 177 0.0092 178 0.0036 182 0.0081 185 0.0039 Reduction of NE-Example activity in U937 cells 1050 [AM]
I-187 0.0073 H
188 0.0044 I-191 0.0033 192 0.0041 193 0.0065 H
196 0.0053 - 217 0.0075 223 0.0030 H
224 0.0010 I-225 0.0028 H
226 0.0018 H
227 0.0009 228 0.0046 H
229 0.0029 H
232 0.0052 I-234 0.0069 H
237 0.0096 H
241 0.0053 245 0.0038 H
247 0.0080 249 0.0165 250 0.0115 253 0.0055 254 0.0305 267 0.0027 268 0.0007 H
269 0.0055 H
270 0.0014 _ 271 0.0017 H
272 0.0024 H
277 0.0036 I-278 0.0010 Reduction of NE-Example activity in U937 cells 1050 ljaMJ
I-279 0.0019 -281 0.0019 H
282 0.0034 H
283 0.0045 284 0.0053 289 0.0039 H
293 0.0046 H
294 0.0078 H
- 295 0.0086 300 0.0089 H
303 0.0083 H
319 0.0093 320 0.0037 H
322 0.0021 I-323 0.0014 H
324 0.0013 H
- 325 0.0047 326 0.0019 H
328 0.0012 329 0.0025 330 0.0377 H
331 0.0060 I-332 0.0058 333 0.0047 H
- 339 0.0006 340 0.0008 H
342 0.0247 H
343 0.0169 I-344 0.0041 H
345 0.0069 H
346 0.0068 Reduction of NE-Example activity in U937 cells 348 0.0020 349 0.0028 358 0.0037 359 0.0029 W009074829; Example 56 0.1067 INHIBITION OF HUMAN CATHEPSIN K
Materials: Microtiterplates (Optiplate-384 F were purchased from PerkinElmer (Prod.No.
6007270). The substrate Z-Gly-Pro-Arg-AMC was from Biomol (Prod.-No. P-142). L-Cysteine (Prod.No. 168149) was from Sigma. Sodium actetate was from Merck (Prod.-No.
6268.0250), EDTA was from Fluka (Prod.-No. 03680). The inhibitor E-64 was purchased from Sigma (Prod.-No. E3132). The recombinant human Cathepsin K proenzyme was purchased from Biomol io (Prod.No. SE-367). All other materials were of highest grade commercially available.
The following buffers were used: Activation buffer: 32.5 mM sodium acetate, adjusted to pH 3.5 with HCI; Assay buffer: 150 mM sodium acetate, 4mM EDTA, 20 mM L-Cysteine, adjusted to pH
5.5 with HC1, Assay conditions: To activate the proenzyme, 5 illprocathepsin K were mixed with lul activation buffer, and incubated at room temperature for 30 min.
5 litL test compound (final concentration 0.1 nM to 100 j.(M) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uL of Cathepsin K in assay buffer (final concentration 2 ng/ L) and incubated for 10 min. Then 5 ILLL of substrate in assay buffer (final concentration 12.5 !AI) were added. The plates were then incubated at room temperature for 60min. Then, the reaction was stopped by adding 10 jiL of E64 in assay buffer (final concentration 1 ,M). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm).

Each assay microtiter plate contains wells with vehicle controls (1% DMSO in bidest) as reference for non-inhibited enzyme activity (100% Ctl; high values) and wells with inhibitor (E64 in bidest +
1% DMSO, final concentration 1 p,M) as controls for background fluorescence (0% Ctl; low values). The analysis of the data was performed by calculating the percentage of fluorescence in the presence of test compound in comparison to the fluorescence of the vehicle control after subtracting the background fluorescence:
(RFU(samp1e)-RFU(background))*100/(RFU(control)-RFU(background)) to Data from these calculations were used to generate IC50 values for inhibition of Cathepsin K, respectively.
Table 68 Inhibition of Cathepsin K
Example 2 2.8 3 2.1 4 2.6 5 2.6 6 2.5 7 8.0 2.7 11 2.6 12 2.1 13 3.4 14 2.7 3.2 16 2.1 17 6.1 18 3.0 19 5.4 2.9

21 4.9

22 3.2 Inhibition of Cathepsin K
Example IC50 [gni

23 3.8

24 13.3 H

25 6.3 _

26 3.6 H

27 3.2 H

28 2.7

29 1.4 H

30 3.1 I--

31 7.3 I-

32 3.9 H

33 4.8 _

34 2.5 H

35 4.4 H

36 3.0

37 5.1 H

38 2.9 I--

39 7.8 H

40 7.8

41 4.7 I--

42 2.9 H

43 2.2 H

44 4.0

45 4.4 I-

46 4.0 H

47 3.4 H

48 3.3 H

49 6.5 _

50 3.6

51 4.9

52 17.0

53 4.1 Inhibition of Cathepsin K
Example IC50 [gni

54 4.5

55 3.9 H

56 4.0 _

57 2.3 H

58 11.1 H

59 2.5

60 12.3 H

61 10.9 I--

62 3.9 I-

63 6.2 H

64 4.2 _

65 11.7 H

66 4.8 H

67 4.6

68 7.3 H

69 2.4 I--

70 12.0 H

71 4.8

72 7.3 I--

73 3.1 H

74 2.5 H

75 5.3

76 5.3 I-

77 5.3 H

78 6.7 H

79 3.5 H

80 4.1 _

81 4.5

82 5.4

83 5.1

84 4.9 Inhibition of Cathepsin K
Example IC50 [gni

85 3.0

86 6.8 H
88 8.8 _ 89 5.4 H
90 3.5 H
91 2.5 92 8.2 H
93 6.9 I--94 4.9 I-95 3.6 H
96 5.5 _ 97 7.9 H
98 8.4 H
99 2.9 100 8.2 H
101 6.5 I--102 4.3 H
103 5.9 104 10.3 I--105 5.2 H
106 5.3 H
107 4.7 108 9.4 I-109 4.5 H
110 9.8 H
111 4.3 H
112 5.6 _ 113 8.3 114 6.8 115 2.3 116 7.7 Inhibition of Cathepsin K
Example IC50 [gni 117 2.7 118 3.9 H
119 4.5 _ 121 5.2 H
130 10.2 H
132 12.2 133 19.4 H
134 6.7 I--136 6.2 I-138 6.4 H
139 4.8 _ 140 8.4 H
141 8.8 H
143 5.1 144 11.1 H
145 7.4 I--146 9.6 H
147 9.7 148 14.6 I--149 7.6 H
150 9.3 H
151 4.8 152 6.1 I-153 4.4 H
154 4.6 H
155 1.0 H
156 7.8 _ 157 7.4 158 9.4 159 3.3 161 10.7 Inhibition of Cathepsin K
Example IC50 [gni 167 6.3 169 5.2 H
176 13.9 _ 181 9.7 H
182 3.5 H
185 1.7 186 3.5 H
190 3.7 I--193 2.2 I-199 11.7 H
200 3.3 _ 201 2.5 H
203 8.4 H
218 26.0 222 1.7 H
228 2.0 I--229 1.6 H
230 5.9 231 2.4 I--233 3.0 H
234 2.9 H
235 3.0 236 1.7 I-237 1.9 H
238 9.3 H
239 2.0 H
240 9.4 _ 241 2.5 242 2.5 244 2.0 245 1.2 Inhibition of Cathepsin K
Example IC50 [gni 247 4.5 249 3.6 H
250 3.1 _ 252 3.3 H
253 5.7 H
254 4.5 259 3.7 H
260 3.9 I--261 3.8 I-262 2.8 H
263 2.1 _ 267 4.7 H
268 3.8 H
269 1.7 270 6.1 H
274 3.5 I--276 5.5 H
278 1.2 281 1.9 I--282 1.8 H
283 3.6 H
285 8.7 288 2.2 I-293 2.7 H
294 2.2 H
295 4.7 H
296 >30.0 _ 297 12.4 298 17.6 300 23.1 301 19.5 Inhibition of Cathepsin K
Example IC50 [gni 303 22.2 315 >30.0 319 4.5 322 Li 323 0.9 324 0.8 325 2.3 326 1.1 328 7.7 330 6.6 331 1.5 332 6.2 333 2.4 343 5.3 344 6.2 345 9.2 346 4.0 348 4.3 349 5.0 358 9.6 359 6.3 W009074829; Example 56 0.4 DETERMINATION OF METABOLIC STABILITY WITH HUMAN LIVER MICROSOMES
The metabolic degradation of the test compound is assayed at 37 C with pooled human liver microsomes. The final incubation volume of 100 Riper time point contains TRIS
buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg/m1) and the test compound at a final concentration of 1 M. Following a short preincubation period at 37 C, the reactions are initiated by addition of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM) and terminated by transfering an aliquot into acetonitrile after different time points. Additionally, the NADPH-independent degradation is monitored in incubations without NADPH, terminated at the last time point. The [%] remaining test compound after NADPH independent incubation is reflected by the parameter c(control) (metabolic stability). The quenched incubations are pelleted by centrifugation (10'000 g, 5 min). An aliquot of the supernatant is assayed by LC-MS/MS for the amount of parent compound.
The half-life (t1/2 INVITRO) is determined by the slope of the semilogarithmic plot of the concentration-time profile. The intrinsic clearance (CL _INTRINSIC) is calculated by considering the amount of protein in the incubation:
CL_INTRINSIC [ 1/miri/mg protein] = (In 2 / (half-life [min] * protein content [mg/mI])) *1'000.
The half-life (t1/2 INVITRO) values of selected compounds in the metabolic stability assay described above are listed in the following table Table 69 In vitro stability in human liver Example microsome incubations t1/2 [min]
2 >125 4 >130 6 >130 9 >120 10 >130 12 >130 14 >130 16 >130 19 >130 21 >130 22 >130 28 >130 29 >130 In vitro stability in human liver Example microsome incubations t1/2 [min]
I-33 >130 -35 >130 H
40 >130 H
41 >130 42 >130 43 >130 H
44 >130 H

H
49 >130 -50 >130 H
52 >130 H
53 >130 54 >130 H
55 >130 I-H
58 >130 H
62 >130 -H
71 >120 77 >130 H

I-82 >130 83 >130 H
86 >130 -88 >130 H
89 >130 H
90 >130 I-91 >130 H
95 >130 H

In vitro stability in human liver Example microsome incubations t1/2 [min]
I-97 >130 -98 >130 H
99 >130 H
100 >130 102 >130 105 >130 H
106 >130 H
108 >130 H
109 >130 -110 >130 H
111 >130 H
112 >130 114 >130 H
116 >130 I-117 >130 H
125 >130 H
132 >130 -136 >130 H
139 >130 143 >130 147 >130 H
152 >130 I-154 >130 H

H
157 >130 H
158 >130 I-159 >130 H
162 >130 H

In vitro stability in human liver Example microsome incubations t1/2 [min]
I-167 >130 -169 >130 H

H
176 >130 178 >130 180 >120 H
181 >130 H
182 >130 H
183 >130 -184 >130 H
185 >130 H

189 >130 H
190 >130 I-H
192 >130 H
193 >130 -H
196 >130 200 >130 H
201 >130 I-204 >130 205 >130 H
218 >130 -221 >130 H
222 >130 H
223 >130 I-230 >130 H
231 >130 H
233 >130 In vitro stability in human liver Example microsome incubations t1/2 [min]
I-235 >130 -236 >130 H

H
239 >130 H
242 >130 H

H
245 >130 -247 >130 H
248 >130 H
249 >130 250 >130 H

I-253 >130 H
254 >130 H
255 >130 -258 >130 H
259 >130 260 >130 261 >130 H
262 >120 I-263 >130 266 >130 H
267 >130 -268 >130 H
269 >130 H
270 >130 I-H
272 >130 H
274 >125 In vitro stability in human liver Example microsome incubations t1/2 [min]
I--277 >130 H
278 >130 H
281 >130 282 >130 283 >130 H

H
285 >130 H
288 >130 -H
291 >130 H

293 >130 H
294 >130 I-295 >130 H
296 >130 H

-300 >130 H

303 >130 H
306 >130 I-307 >130 308 >130 H
310 >130 -313 >130 H
314 >130 H

I-319 >130 H
320 >130 H
321 >130 In vitro stability in human liver Example microsome incubations t1/2 [min]
322 >130 323 >130 324 >130 325 >130 327 >130 328 >130 330 >130 331 >120 333 >130 335 >130 341 >130 342 >130 343 >130 345 >130 346 >130 347 >130 349 >130 358 >130 359 >130 W009074829; Example 56 120 COMBINATIONS
The compounds of general formula I may be used on their own or combined with other active substances of formula I according to the invention. The compounds of general formula I may optionally also be combined with other pharmacologically active substances.
These include, B2-adrenoceptor-agonists (short and long-acting), anti-cholinergics (short and long-acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7-inhibitors, LTD4 antagonists, EGFR- inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3-receptor antagonists, P13-kinasc inhibitors, inhibitors of non-receptor tyrosine kinases as for example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAP kinases as for example p38, ERK1, ERK2, JNK1, INK2, JNK3 or SAP, inhibitors of the NF-K13 signalling pathway as for example IKK2 kinase inhibitors, io iNOS inhibitors, MRP4 inhibitors, leukotriene biosynthese inhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors, Non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists, DP1-receptor modulators, Thromboxane receptor antagonists, CCR3 antagonists, antagonists, CCR1 antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30 antagonists_ CXCR3 antagonists, CXCR4 antagonists, CXCR2 antagonists, CXCR1 antagonists, CXCR5 antagonists, CXCR6 antagonists, antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1-Phosphate receptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulators as for example A2a-agonists, modulators of purinergic rezeptors as for example P2X7 inhibitors, Histone Deacetylase (HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE
inhibitors, PPAR
gamma modulators, Rho-kinase inhibitors, interleukin 1-beta converting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAa receptor antagonist, ENaC-inhibitors, Prostasin-inhibitors, Matriptase-inhibitors, Melanocortin receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists, TNFot antagonists, anti-TNF
antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-0X40 antibodies, mucoregulators, immunotherapeutic agents, compounds against swelling of the airways, compounds against cough, VEGF inhibitors, NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinations of two or three active substances.
Preferred are betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors, NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinations of two or three active substances, i.e.:
= Betamimetics with corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists, = Anticholinergics with betamimetics, corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists, = Corticosteroids with PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists = PDE4-inhibitors with CRTH2-inhibitors or LTD4-antagonists = CRTH2-inhibitors with LTD4-antagonists.
INDICATIONS
The compounds of the invention and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as inhibitors of dipeptidyl peptidase I
activity, and thus may be used in the treatment of 1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD);
bronchitis, including infectious and eosinophilic bronchitis; emphysema;
alphal-antitrypsin deficiency, bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
hypersensitivity pncumonitis; lung fibrosis, including cryptogcnic fibrosing alvcolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections;
complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, polyangiitis (Wegener Granulomatosis) and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough;
acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
2. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis;
seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme;
cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
3. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis;
anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders ni .. affecting the retina; ophthalmitis including sympathetic ophthalmitis;
sarcoidosis; infections including viral, fungal, and bacterial;
4. genitourinary: nephritis including interstitial and glomerulonephritis;
nephrotic syndrome;
cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease;
erectile dysfunction (both male and female);
5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
6. other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-lgE syndrome, antiphospholipid syndrome and Sazary syndrome;
7. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 8. infectious diseases: virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
9. pain: Recent literature data from Cathepsin C-deficient mice point to a modulatory role of Cathepsin C in pain sensation. Accordingly, inhibitors of Cathepsin C may also be useful in the clinical setting of various form of chronic pain, e.g. inflammatory or neuropathic pain.
For treatment of the above-described diseases and conditions, a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20 mg/kg of body weight per dosage. For Example, for administration to a 70 kg person, the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern. The active ingredient may be administered from 1 to 6 times a day.
The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the active ingredient will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.

Claims

CLAIMS:

1. A compound of formula 1 wherein is independently selected from H, C1_6-alkyl-, halogen, HO-, C1_6-alky1-0-, H2N-, C1_6-alkyl-HN-, (C1_6-alky1)2N- and Ci_6-alkyl-C(0)HN-;
or two RI are together C1_4-alkylene;
R2 is selected from = R2 1;
= aryl-; optionally substituted with one, two, three or four independently selected R21; and optionally substituted with one R23;
= C5-10-heteroaryl-; containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two, three or four R21 on available carbon atoms; optionally and independently from each other substituted with one, two or three R22 on available nitrogen atoms; and optionally substituted with one R23 on available carbon atoms and optionally substituted with one R24 on available nitrogen atoms; and = C5_10-heterocycly1-; containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two, three or four R21 on available carbon atoms; optionally and independently from each other substituted with one, two or three R22 on available nitrogen atoms; and optionally substituted with one R23 or one R2 5 on available carbon atoms or with one R2 4 on available nitrogen atoms, or = R2 and R4 are together with two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two Date Recue/Date Received 2022-05-06 or three R2A on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2' on available nitrogen atoms;
R2.1 is independently selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-C1_6-alkylene-, R2-1-1-A-, C1_6-alkyl-A-, C3_8-cycloalkyl-A-, C1_6-haloalkyl-A-, R2-1-1-C1_6-alkylene-A-, C1_6-alkyl-A-C1_6-alkylene-, C3_8-cycloalkyl-A-C1_6-alkylene-, C1_6-haloalkyl-A-C1_6-alkylene-, R2=1=1-C1_6-alkylene-A-C1_6-alkylene-, R2-1-1-A-C1_6-alkylene-, HO-C1_6-alkylene-A-, HO-C1_6-alkylene-A-C1_6-alkylene-, C1_6-alkyl-O-C1_6-alkylene-A- and C1_6-alkyl-O-C1_6-alkylene-A-C1_6-alkylene-R2.1.1 is independently selected from = aryl-; optionally substituted independently from each other with one, two or three R2.1.1.1;
= C5-10-heteroaryl-; containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two or three R2.1.1.1 on available carbon atoms;
and optionally and independently from each other substituted with one, two or three R2.1.1.2 on available nitrogen atoms; and = C5-10-heterocyclyl-; containing one, two, three or four heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two or three or four R2.1.1.1 on available carbon atoms;
and optionally and independently from each other substituted with one, two or three R2.1.1.2 on available nitrogen atoms;
R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_6-haloalkyl-, C1_6-haloalkyl-0- and C3_8-cycloa1kyl-;
R2.1.1.2 is independently selected from 0=, C1_6-alkyl-, C1_6-haloalkyl-;
C1_6-alkyl-O-C1_6-alkyl-, H(0)C-, C1_6-alkyl-(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;
R2.2 is independently selected from H-A-C1_6-a1kylene-, C3-8-cycloalkyl-A-C1-6-a1kylene-, Date Recue/Date Received 2022-05-06 C1_6-haloalkyl-A-C1_6-alkylene-, C1_6-alkyl-S(0)2-, C1_6-alkyl-C(0)- and R2-1-1-A-;
R2-3 is together with R4 selected from -0-, - S-, -N(R2-3-1)-, -C(0)N(R2-3-1)-, -N(R2-3-1)C(0)-, -S(0)2N(R2-3-')-, -N(R2-3-1)S(0)2-, -C(0)0-, -0C(0)-, -C(0)-, -S(0)-, -S(0)2-, -C(R2-3-2)=C(R2-3-2)-, -C=N-, -N=C-, -C(R2-3-2)2-0-, -0-C(R2-3-2)2-, -C(R2-3-2)2N(R2-3-1)-, -N(R2-3-1)C(R2-3-2)2- and -C1_4-alkylene-;
R2.3.1 is independently selected from H, C1-6-haloa1kyl-; C3_8-cycloa1kyl-, HO-C1_4-a1kylene-, (C1_4-a1kyl)-0-C1_4-a1kylene-, H2N-C1_4-a1kylene-, (C1_4-alkyOHN-C1_4-a1kylene- and (C1-4-a1kyl)2N-C1-4-a1kylene-;
R2.3.2 is independently selected from H, C1_6-haloa1kyl-; C3_8-cycloa1kyl-, HO-C1_4-a1kylene-, (C1_4-a1kyl)-0-C1_4-a1kylene-, H2N-C1-4-a1kylene-, (C1_4-alkyOHN-C1_4-a1kylene- and (C1-4-a1kyl)2N-C1-4-a1kylene-;
R24 is together with R4 selected from -C(0)N(R2-4-1)-, -N(R2-4-1)C(0)-, -S(0)2N(R2-4-1)-, -N(R2-4-1)S(0)2-, -C(0)-, -S(0)-, -S(0)2-, -C(R2-4-2)=C(R2-4-2)-, -C(R2-4-2)2N(R2-4-1)-, -N(R2-4-1)C(R2-4-2)2- and -C1_4-a1kylene-;
R2.4.1 is independently selected from H, C1_6-haloa1kyl-;
HO-C1_4-a1kylene-, (C1_4-a1kyl)-0-Ci_4-a1kylene-, H2N-C1-4-a1kylene-, (C1_4-alkyOHN-C1_4-a1kylene- and (C1-4-a1kyl)2N-C1-4-a1kylene-;
R2.4.2 is independently selected from H, C1_6-haloa1kyl-;
HO-C1_4-a1kylene-, (C1_4-a1kyl)-0-Ci_4-a1kylene-, H2N-C1-4-a1kylene-, (C1_4-alkyOHN-C1_4-a1kylene- and (C1-4-a1kyl)2N-C1-4-a1kylene-;
R2-5 is together with R4 selected from -C(R2-5-1)=, =C(R2-5-1)- and -N=; and R2.5.1 is independently selected from H, C1-6-haloa1kyl-;
HO-C1_4-a1kylene-, (C1_4-a1kyl)-0-C1_4-a1kylene-, H2N-C1_4-a1kylene-, (C1_4-alkyOHN-C1_4-a1kylene- and (C1-4-a1kyl)2N-C1-4-a1kylene-;
Date Recue/Date Received 2022-05-06 R3 is H or F;
R4 is independently selected from F, Cl, phenyl-H2C-0-, HO-, Ci_6-alkyl-, C1_6-haloalkyl-, C3_8-cycloalkyl-, Ci_6-alky1-0-, Ci_6-haloalky1-0-, (C1_6-alky02-HN-, Ci_6-alkyl-HN-Ci_4-alkylene- and (Ci_6-alky1)2-HN-Ci_4-alkylene-;
A is a bond or independently selected from -0-, - S-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R5)S(0)2-, -S(0)(=NR5)-N(R5)-, -N(R5)(NR5=) S(0)-, -S(=NR5)2-N(R5)-, -N(R5)(NR5=)25-, -C(R5)=C(R5)-, -CC-õ -C(0)0-, -0C(0)-, -C(0)-, -S(0)-, -S(0)2-, -S(=NR5)-, -S(0)(=NR5)-, -S(=NR5)2-, -(R5)(0)S=N-, -(R5N=)(0)S-, and-N=(0)(R5)S-;
R5 is independently selected from H, C1-6-a1kyl- and NC-;
or a salt thereof.

2. A compound of formula 1, according to claim 1, wherein R1 is independently selected from H, Ci_4-alkyl-, F and HO-.

3. A compound of formula 1, according to claim 1 or 2, wherein A is Aa and Aa is a bond or independently selected from -0-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)-, -N(R5)S(0)2-, -C(0)0-, -0C(0)-, -C(0)-, -S(0)2-, -(R5)(0)S=N-, -(R5N=)(0)S-and -N=(0)(R5)S-, and wherein R5 is R5 a and RS a is independently selected from H, Ci_4-a1kyl- and NC-.

4. A compound of formula 1, according to any one of claims 1 to 3, wherein R4 is R4 a and R4 a is F, Cl, phenyl-H2C-0-, HO-, C1_4-a1kyl-, Ci_4-haloalkyl-, C3_6-cycloa1kyl-, Ci_4-alky1-0- or Ci_4-haloalky1-0-.

5. A compound of formula 1, according to any one of claims 1 to 4, wherein R4 is F.

6. A compound of formula 1, according to any one of claims 1 to 5, wherein R2 is R21 and R2 is R21 a and R21 a is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-Ci_4-alkylene-, R211-A-, C1_4-a1kyl-A-, R211-C14-a1kylene-A-, C14-a1kyl-A-C14-a1kylene-, C3-6-cycloalkyl-A-C1-4-alkylene-, C14-ha1oa1ky1-A-C14-a1ky1ene-, R2 II-C1_4-alkylene-A-C1_4-alkylene-, R2 II-A-C1_4-alkylene-, HO-Ci_4-a1ky1ene-A-, HO-CI4-alkylene-A-C14-alkylene-, Ci_4-alkyl-O-Ci_4-a1kylene-A- and C1_4-a1ky1-0-C14-a1kylene-A-C14-a1kylene-; and Date Recue/Date Received 2022-05-06 R2.1.1 is R2.1.1.a and R2.1.1.a is selected from = aryl-, optionally substituted independently from each other with one, two or three independently selected R21.1.1;
= C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two or three R2.1.1.1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2.1.1.2 on available nitrogen atoms; and = C5_lo-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two or three R2.1.1.1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-1-1' on available nitrogen atoms; and R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_4-alkyl-, C1_4-alky1-0-, C14-haloalkyl-, C14-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C14-haloalkyl-; C3_6-cycloalkyl-, C1_4-alkyl-O-C1_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl-and tetrahydropyranylmethyl.

7. A compound of formula 1, according to any one of claims 1 to 5, wherein R 2 is R2-d and R'd is phenyl;
optionally substituted with one, two or three independently selected R2.1 and R2.1 is R2.1.a and R2-1-a is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-Ch4-alkylene-, C1_4-alkyl-A-, C3_6-cycloalkyl-A-, R2-12-C1_4-a1kylene-A-, C1_4-alkyl-A-C1_4-alkylene-, C3-6-cycloalkyl-A-C1-4-alkylene-, C1_4-ha1oa1ky1-A-C14-a1ky1ene-, R2-12-C1_4-alkylene-A-C1_4-alkylene-, R2-12-A-C1_4-alkylene-, HO-CI4-alkylene-A-C1_4-alkylene-, C1_4-alkyl-O-C14-alkylene-A- and C1_4-alkyl-O-C1_4-alkylene-A-C1_4-alkylene-; and R2.1.1 is R2.1.1.a and R2.1.1.a is selected from = aryl-, optionally substituted independently from each other with one, two or three independently selected R21.1.1;
= C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two Date Recue/Date Received 2022-05-06 or three R2-1-1-1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-1-1-2 on available nitrogen atoms; and = C54o-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two or three R2-1-1-1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-1-1' on available nitrogen atoms; and R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_4-alkyl-, C1_4-alky1-0-, C1_4-haloalkyl-, C1_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.11.2 is independently selected from 0=, C14-haloalkyl-; C3_6-cycloalkyl-, C1_4-alkyl-O-C1_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl-and tetrahydropyranylmethyl.

8. A compound of formula 1, according to any one of claims 1 to 5, wherein R2 is R2-g and R2-g is selected from wherein R2-g is optionally and independently from each other substituted with one, two or three R2A on available carbon atoms; and where possible optionally and independently from each other substituted with one, two or three R2' on available nitrogen atoms; and R2.1 is R2-1-a and R2-1-a is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-Ch4-alkylene-, R2-1-1-A-, C1_4-alkyl-A-, C3_6-cycloalkyl-A-, C3-6-cycloalkyl-A-C1-4-alkylene-, C1_4-ha1oa1ky1-A-C14-a1ky1ene-, R2.1.1-C1_4-alkylene-A-C1_4-alkylene-, R2-1-1-A-C1_4-alkylene-, HO-Ci_4-a1ky1ene-A-, HO-CI4-alkylene-A-C1_4-alkylene-, Ci_4-alkyl-O-C14-a1kylene-A- and C1_4-a1kyl-O-C1_4-a1kylene-A-C1_4-a1kylene-; and Date Recue/Date Received 2022-05-06 R2.1.1 is R2.1.1.a and R2.1.1.a is selected from = aryl-, optionally substituted independently from each other with one, two or three independently selected R21.1.1;
= C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two or three R2.1.1.1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2.11.2 on available nitrogen atoms; and = C54o-heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two or three R211.1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-1-1' on available nitrogen atoms; and R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_4-alkyl-, C1_4-alkyl-0-, C1_4-haloalkyl-, C1_4-haloalkyl-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C14-haloalkyl-; C3_6-cycloalkyl-, C1_4-alkyl-O-C1_4-alkyl-, H(0)C-, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R2.2 is R2.2.a. and R2.2.a. is independently selected from H-A-C1_4-alkylene-, C3_6-cycloalkyl-, C3_6-cycloa1kyl-A-C1_4-a1kylene-, C1_4-alkyl-S(0)2-, C1_4-a1kyl-C(0)- and R2-1-1-A-.

9. A compound of formula 1, according to any one of claims 1 to 5, wherein R2 is R21 and R21 is selected from wherein R21 is optionally and independently from each other substituted with one, two or three R2-' on available carbon atoms; and where possible optionally and independently from each other substituted with one, two or three R2' on available nitrogen atoms; and R2.1 is R2-1-a and R2-1-a is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-C1_4-alkylene-, R2-1-1-A-, C1_4-alkyl-A-, C3_6-cycloalkyl-A-, C1_4-haloalkyl-A-, R2-1-1-C1_4-alkylene-A-, C1_4-alkyl-A-C1_4-alkylene-, C3_6-cycloalkyl-A-C1_4-alkylene-, C1_4-ha1oa1ky1-A-C14-a1ky1ene-, R2-1-1-C1_4-alkylene-A-C1_4-alkylene-, R2-1-1-A-C1_4-alkylene-, HO-Ci_4-a1ky1ene-A-, HO-CI4-alkylene-A-C1_4-alkylene-, C1_4-alkyl-O-C14-alkylene-A- and C1_4-alkyl-O-C1_4-alkylene-A-C1_4-alkylene-; and R2.1.1 is R2.1.1.a and R2.1.1.a is selected from = aryl-, optionally substituted independently from each other with one, two or three independently selected R2-1-1-1;
= C540-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two or three R2-1-1-1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-1-1-2 on available nitrogen atoms; and = C5-10-heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two or three R2-1-1-1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-1-1' on available nitrogen atoms; and Date Recue/Date Received 2022-05-06 R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_4-alkyl-, C1_4-alky1-0-, C1_4-haloalkyl-, C1_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C14-haloalkyl-; C3_6-cycloalkyl-, C1_4-alkyl-O-C1_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl-and tetrahydropyranylmethyl; and R2.2 is R2.2.a and R2.2.a. is independently selected from H-A-C1_4-alkylene-, C3_6-cycloalkyl-, C3_6-cycloa1kyl-A-C1_4-a1kylene-, C1_4-alkyl-S(0)2-, C1_4-a1kyl-C(0)- and R2-1-1-A-.

10. A compound of formula 1, according to any one of claims 1 to 3, wherein R2 is R2-m and R2-m is together with R4 and two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S(0), S(0)2, 0 and N, wherein R' is optionally and independently from each other substituted with one, two or three R21 on available carbon atoms, and where possible optionally and independently from each other substituted with one, two or three R22 on available nitrogen atoms; and R2.1 is R2A.a and R2A.a is selected from H, halogen, NC-, 0=, HO-, H-A-, R2-1-1-A-, C1_4-a1kyl-A-, C3_6-cycloalkyl-A-, C1_4-a1kyl-A-C1_4-a1kylene-, R2-1-1-C1_4-alkylene-A-C1_4-a1kylene-, R2-1-1-A-C1_4-alkylene-, HO-C1_4-alkylene-A-C1_4-alkylene-, C1_4-alkyl-O-C14-a1kylene-A- and C1_4-a1kyl-O-C1_4-a1kylene-A-C1_4-a1kylene-; and R2.1.1 is R2.1.1.a and R2.1.1.a is selected from = aryl-, optionally substituted independently from each other with one, two or three independently selected R2AAA;
= C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two or three R2AAA on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2A1=2 on available nitrogen atoms; and = C54o-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two or three R2AAA on available carbon Date Recue/Date Received 2022-05-06 atoms; and optionally and independently from each other substituted with one, two or three R2112 on available nitrogen atoms; and R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_4-alkyl-, C1_4-alky1-0-, C1_4-haloalkyl-, C1_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C14-alkyl-, C14-haloalkyl-; C3_6-cycloalkyl-, C1_4-alkyl-O-C1_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl-and tetrahydropyranylmethyl; and R2.2 is R2.2.a and R2.2.a. is independently selected from H-A-C1_4-alkylene-, C3_6-cycloalkyl-, C1_4-alkyl-A-C14-alkylene-, C3_6-cycloa1kyl-A-C1_4-a1kylene-, C1_4-alkyl-S(0)2-, C1_4-a1kyl-C(0)- and R2-1-1-A-.

11. A compound of formula 1, according to any one of claims 1 to 3, wherein R2 is R2-ll and R2-ll is selected from aryl-, pyrazole, thiophene, and furane; wherein R' is optionally and independently from each other substituted with one, two, three or four R2A on available carbon atoms; where possible optionally and independently from each other substituted with one, two or three R2' on available nitrogen atoms; and optionally substituted with one R2.3 on available carbon atoms or with one R2-4 on available nitrogen atoms;
or R' is selected from wherein R2-ll is optionally and independently from each other substituted with one, two, three or four R2.1 on available carbon atoms; where possible optionally and independently from each other substituted with one, two or three R2' on available nitrogen atoms; and optionally substituted with one R2-3or one R2-5 on available carbon atoms or with one R24 on available nitrogen atoms; and R2.1 is R2.1.a and R2-1-a is selected from H, halogen, NC-, 0=, HO-, H-A-, R2-1-1-A-, C1_4-a1kyl-A-, C3_6-cycloalkyl-A-, C3-6-cycloalkyl-A-C1-4-alkylene-, C1_4-haloa1kyl-A-C14-a1kylene-, R2-1-1-C1_4-a1ky1ene-A-C1_4-a1ky1ene-, R2-1-1-A-C1_4-alkylene-, HO-Ci_4-a1ky1ene-A-, Date Recue/Date Received 2022-05-06 HO-C1_4-alkylene-A-C1_4-alkylene-, C1_4-alkyl-O-C14-alkylene-A- and Ci_4-alkyl-O-Ci_4-alkylene-A-C1_4-alkylene-; and R2.1.1 is R2.1.1.a and R2.1.1.a is selected from = aryl-, optionally substituted independently from each other with one, two or three independently selected R2A-1-1;
= C54o-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two or three R2-1-1-1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-1-1-2 on available nitrogen atoms; and = C54o-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N and the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two or three R2-1-1-1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-1-12 on available nitrogen atoms; and R2.1.1.1 is independently selected from halogen, HO-, 0=, Ci_4-alkyl-, Ci_4-alky1-0-, C1_4-haloalkyl-, C1_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C14-haloalkyl-; C3_6-cycloalkyl-, C1_4-alkyl-O-Ci_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl-and tetrahydropyranylmethyl; and R2.2 is R222 and R2-22 is independently selected from H-A-C1_4-alkylene-, C14-alkyl-A-C1_4-alkylene-, C3_6-cycloalkyl-A-C14-alkylene-, R2-1-1-A-C1_4-alkylene-, C1_4-alkyl-S(0)2-, C1_4-alkyl-C(0)- and R2-n-A-; and R2-3 is together with R4 a group R2-32 and R2-32 is selected from -0-, - S-, -N(R2-3-1)-, -C(0)N(R23-1)-, -N(R2-3-1)C(0)-, -S(0)2N(R2-3-1)-, -N(R2-3-1)S(0)2-, -C(0)0-, -0C(0)-, -C(0)-, -S(0)-, -S(0)2-, -C(R2.32)=C(R2-32)-, -C=N-, -N=C-, -C(R2-32)2-0-, -0-C(R2-32)2-, -C(R2-32)2N(R2-3-1)-, -N(R23-1)C(R2-32)2-and -C1_4-alkylene-; and R2.3.1 is independently selected from H, C1_4-haloa1kyl-, C3_6-cycloalkyl-, HO-C1_4-alkylene-, (C1-4-a1kyl)-0-C1_4-alkylene-, H2N-C14-a1kylene-, (Ci_4-alkyl)HN-Ci_4-alkylene- and (Ci_4-a1ky1)2N-Ci_4-a1kylene-;
Date Recue/Date Received 2022-05-06 R2.3.2 is independently selected from H, C1_4-alkyl-, C1_4-haloalkyl-, C3_6-cycloalkyl-, HO-C1_4-alkylene-, (C1-4-alkyl)-0-C1_4-alkylene-, H2N-Ci_4-alkylene-, (C1_4-alkyOHN-C1_4-alkylene- and (Ci_4-alky1)2N-Ci_4-alkylene-; and R24 is together with R4 a group R2.42 and R2-42 is selected from -N(R2-4-1)-, -C(0)N(R2-4-1)-, -N(R2A.1)C(0)_, _S(0)2N(R2-4-1)-, -N(t2.4.1)s(0)2_, -S(0)2-, -C(R2-42)=C(R2A).2µ -C=N-, -N=C-, -C(R24.2)2N(R24.1)_, _NR2A.1)C(R2A).2,2-and -C1_4-alkylene-; and R24.1 is independently selected from H, C1_4-alkyl-, C1_4-haloalkyl-, C3_6-cycloalkyl-, HO-C1_4-alkylene-, (C1-4-alkyl)-0-C1_4-alkylene-, H2N-C1_4-alkylene-, (C1_4-alkyOHN-C1_4-alkylene- and (C1_4-alky1)2N-Ci_4-alkylene-;
R24.2 is independently selected from H, C1_4-alkyl-, C1_4-haloalkyl-, C3_6-cycloalkyl-, HO-C1_4-alkylene-, (C1-4-alkyl)-0-C1_4-alkylene-, H2N-C1_4-alkylene-, (Ci_4-alkyl)HN-Ci_4-alkylene- and (C1_4-alky1)2N-Ci_4-alkylene-; and R2-5 is together with R4 a group R2-52 and R2-52 is selected from -C(R2-5-1)=, =C(R2-5-1)- and -N=;
and R2.5.1 is independently selected from H, Ci_4-alkyl-, Ci_4-haloalkyl-, C3_6-cycloalkyl-, HO-C1_4-alkylene-, (C1-4-alkyl)-0-C1_4-alkylene-, H2N-C1_4-alkylene-, (C1_4-alkyl)HN-C1_4-alkylene- and (C1_4-alky1)2N-Ci_4-alkylene-.

12. A compound of formula 1 according to any one of claims 1 to 5, wherein is H;
R2 is R2-`1 and R2.`1 is selected from among the substituents (al) to (ql) wherein R2-q is optionally and independently from each other substituted with one, two, three or four R2A on available carbon atoms; and where possible optionally and independently from each other are substituted with one, two or three R2' on available nitrogen atoms;
or a salt thereof.

13. A compound of formula 1 according to any one of claims 1 to 3, wherein R2 is R2-s and R23 is Phenyl-R2-3, wherein R2-3 is as defined in claim 1 and the phenyl ring is optionally substituted with one or two R2-1, wherein R2.1 is R2-1-a and R2-1 is selected from H, halogen, NC-, 0=, HO-, H-A-, H-A-C1_4-alkylene-, R2-1-1-A-, C1_4-alkyl-A-, C3_6-cycloalkyl-A-, C1_4-haloalkyl-A-, R2-1-1-C1_4-alkylene-A-, C1_4-alkyl-A-C1_4-alkylene-, C3_6-cycloalkyl-A-C1_4-alkylene-, C1_4-haloalkyl-A-C1_4-alkylene-, R2-1-1-C1_4-alkylene-A-C1_4-alkylene-, R2-1-1-A-C1_4-alkylene-, HO-C14-alkylene-A-, HO-C1_4-alkylene-A-C1_4-alkylene-, C1_4-alkyl-O-C1_4-alkylene-A- and C1_4-alkyl-O-C1_4-alkylene-A-C1_4-alkylene-; and R2.1.1 is R2.1.1.a and R2.1.1.a is selected from = aryl-, optionally substituted independently from each other with one, two or three independently selected R2-1-1-1;
= Cs_lo-heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, optionally and independently from each other substituted with one, two or three R2-1-1-1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-112 on available nitrogen atoms;
= C5_lo-heterocycly1-, containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)2, 0 and N, and the ring is fully or partially saturated, and is optionally and independently from each other substituted with one, two or three R2-1-1-1 on available carbon atoms; and optionally and independently from each other substituted with one, two or three R2-112 on available nitrogen atoms; and R2.1.1.1 is independently selected from halogen, HO-, 0=, C1_4-alkyl-, C1_4-alky1-0-, C1_4-haloalkyl-, C1_4-haloalky1-0- and C3_6-cycloalkyl-; and R2.1.1.2 is independently selected from 0=, C14-haloalkyl-; C3_6-cycloalkyl-, C1_4-alkyl-O-C1_4-alkyl-, H(0)C-, C1_4-alkyl-(0)C-, tetrahydrofuranylmethyl-and tetrahydropyranylmethyl;
and R2-s and R4 together denote a group (rl), wherein the N-atom is optionally substituted with ¨R2-2, wherein R2.2 is independently selected from H-A-C1_6-alkylene-, C3_8-cycloa1kyl-, C1_6-alkyl-A-C1_6-a1kylene-, C3_8-cycloalkyl-A-C1_6-a1kylene-, C1_6-haloalkyl-A-C1_6-a1kylene-, R2-1-1-A-C1_6-alkylene-, C1-6-alkyl-S(0)2-, C1-6-alkyl-C(0)- and R2-1-1-A-;
or a salt thereof.
Date Recue/Date Received 2022-05-06

14. A compound of formula 1' wherein R3, R2, R3 and IZ3 are as defined in any one of claims 1 to 12.

15. A compound of formula 1 according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use as a medicament.

16. A compound of formula 1 according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use as a medicament for the treatment of asthma and allergic diseases, gastrointestinal inflammatory diseases, eosinophilic diseases, chronic obstructive pulmonary disease, infection by pathogenic microbes, rheumatoid arthritis or atherosclerosis.

17. Pharmaceutical composition comprising one or more compounds of formula 1 as defined in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. Use of a compound of formula 1 as defined in any one of claims 1-13 for inhibition of dipeptidyl peptidase I (DPPI) activity.

19. A pharmaceutical composition comprising a compound of formula 1, as defined in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically active compound selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagonists, CCR9 antagonists, SYK-inhibitors, NE-inhibitors, MMP9 inhibitors, and MMP12 inhibitors, or combinations of two or three of the pharmaceutically active compounds.
Date Recue/Date Received 2022-05-06